1-cyclopropyl-6-fluoro-8-alkyl-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid derivatives

ABSTRACT

Novel 4-oxoquinoline-3-carboxylic acid compounds of the formula: ##STR1## wherein R 2  is 1-pyrrolidinyl which may have 1 to 2 substituents selected from the group consisting of (i) C 1  -C 6  alkyl, (ii) amino-(C 1  -C 6 )alkyl, said amino being optionally substituted by 1 or 2 substituents selected from C 1  -C 6  alkyl, C 1  -C 6  alkanoyl, and C 1  -C 6  alkoxycarbonyl, (iii) amino which may be substituted by 1 or 2 substituents selected from C 1  -C 6  alkyl, phenyl(C 1  -C 6 )alkyl, C 1  -C 6  alkoxycarbonyl, and C 1  -C 6  alkanoyl, and (iv) 2-oxo-1,3-dioxolenemethylamino which is substituted by C 1  -C 6  alkyl; or 1-piperidinyl which may have 1 to 3 substituents selected from oxo, hydroxy, halogen and C 1  -C 6  alkyl, and R 3  is C 1  -C 6  alkyl, or a pharmaceutically acceptable salt thereof, said compounds having excellent antimicrobial activity and hence being useful as an antimicrobial agent, and a pharmaceutical composition containing said compound as an active ingredient.

This is a Continuation-in-part application of U.S. Ser. No. 017,247filed on Feb. 20, 1987, now abandoned.

The present invention relates to novel antimicrobial benzoheterocycliccompounds of the formula [I]: ##STR2## wherein R² is 1-pyrrolidinylgroup which may have 1 to 3 substituents selected from the groupconsisting of (i) a C₁ -C₆ alkyl group, (ii) an amino-(C₁ -C₆)alkylgroup, said amino group being optinally substituted by 1 to 2substituents selected from the group consisting of a C₁ -C₆ alkyl group,a C₁ -C₆ alkanoyl group, and a C₁ -C₆ alkoxycarbonyl group, (iii) anamino group which may be substituted by 1 or 2 substituents selectedfrom the group consisting of a C₁ -C₆ alkyl group, a phenyl(C₁ -C₆)alkylgroup, a C₁ -C₆ alkoxycarbonyl group, and a C₁ -C₆ alkanoyl group, and(iv) a 2-oxo-1,3-dioxolenemethylamino group which is substituted by a C₁-C₆ alkyl group; or a 1-piperidinyl group which may have 1 to 3substituents selected from the group consisting of oxo, hydroxy, ahalogen and a C₁ -C₆ alkyl, and R³ is a C₁ -C₆ alkyl group, or apharmaceutically acceptable salt thereof.

The benzoheterocyclic compounds of the formula [1] and salts thereofhave excellent antibacterial activities against various gram positiveand gram negative bacteria, and use useful for the treatment of variousinfectious diseases induced by various bacteria in human, other animalsand fish and are also useful as an external antimicrobial ordisinfectant agent for medical instruments or the like.

Prior Art

There are many literatures which disclose 4-oxoquinoline-3-carboxylicacid derivaties useful as antibacterial agents. Among these literatures,U.S. Pat. No. 4,563,459 (=German Pat. No. 3248507) discloses1-cyclopropyl-dihydroquinoline carboxylic acid derivatives of theformula: ##STR3## wherein R₁ is H, F, Cl, Br or NO₂, R² is H, Cl, F orNR³ R⁴ wherein R³ and R⁴ together may form 5- or 6-membered saturated orpartly unsaturated heterocycles.

European Patent Publication No. 153828 (=Japanese Patent FirstPublication (Kokai) No. 214777/1985) discloses1-cyclopropyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid derivativesof the formula: ##STR4## wherein Z is ##STR5## etc., X is CF or N, R¹ isH or lower alkyl.

U.S. Pat. No. 4,556,658 (=Japanese Patent First Publication (Kokai) No.212474/1984) discloses 1-cyclopropyl-3-quinoline carboxylic acidderivatives of the formula: ##STR6## wherein R¹ R² N-- may formheterocyclic groups.

Portugal Pat. No. 80546 (=European Patent Publication No. 195841)discloses quinolone carboxylic acid derivatives of the formula: ##STR7##wherein A is N or CH, R is H or alkyl, R¹ is C₃ -C₆ cycloalkyl, R² is Hor NH₂, and Z is ##STR8## .

Similar 1-cyclopropyl-7-heterocyclic group-substituted dihydroquinolinecarboxylic acid derivatives are also disclosed in other many literaturessuch as Japanese Patent First Publication (Kokai) Nos. 126082/1986 and229877/1986, European Patent Publication Nos. 153163, 172651, 183129,191451, 198192, and 202763, South African Pat. No. 8106080 and 8504792,U.S. Pat. No. 4,578,473, and U.K. Pat. 1,502,405.

BRIEF DESCRIPTION OF THE INVENTION

The object of the present invention is to provide novelbenzoheterocyclic compounds of the formula [1] and salts thereof whichhave excellent antimicrobial activity and excellent absorbability.Another object of the invention is to provide a pharmaceuticalcomposition containing as an active ingredient a compound of the formula[1] or a pharmaceutically acceptable salt thereof, which is useful forthe treatment of various infectious diseases. These and other objects ofthe invention will be apparent to persons skilled in the art from thefollowing description.

DETAILED DESCRIPTION OF THE INVENTION

The novel benzoheterocyclic compounds of the present invention have theformula [1] as mentioned above and include pharmaceutically acceptablesalts thereof.

In the specification, the term "halogen atom" includes fluorine,chlorine, bromine or iodine atom.

The term "C₁ -C₆ alkyl" includes straight chain or branched chain C₁ -C₆alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl, hexyl, etc.

The terms "a 1-pyrrolidinyl group which may have 1 to 3 substituentsselected from the group consisting of (i) a C₁ -C₆ alkyl group, (ii) anamino-(C₁ -C₆)alkyl group, said amino group being optionally substitutedby 1 or 2 substituents selected from the group consisting of a C₁ -C₆alkyl group, a C₁ -C₆ alkanoyl group, and C₁ -C₆ alkoxycarbonyl group,(iii) an amino group which may be substituted by 1 or 2 substituentsselected from the group consisting of a C₁ -C₆ alkyl group, a phenyl(C₁-C₆)alkyl group, a C₁ -C₆ alkoxycarbonyl group, and a C₁ -C₆ alkanoylgroup, and (iv) a 2-oxo-1,3-dioxolenemethylamino group which issubstituted by a C₁ -C₆ alkyl group; or a 1-piperidinyl group which mayhave 1 to 3 substituents selected from the group consisting of oxo,hydroxy, a halogen and a C₁ -C₆ alkyl" include, for example,1-piperidinyl, 1-pyrrolidinyl, 4-methyl-1-piperidinyl,4-ethyl-1-piperidinyl, 4-propyl-1-piperidinyl, 4-n-butyl-1-piperidinyl,4-pentyl-1-piperidinyl, 4-hexyl-1-piperidinyl, 4-hydroxy-1-piperidinyl,3-hydroxy-1-piperidinyl, 2-hydroxy-1-piperidinyl,3,5-dimethyl-1-piperidinyl, 2,5-dimethyl-1-piperidinyl,4-oxo-1-piperidinyl, 3-oxo-1-piperidinyl, 3-amino-1-pyrrolidinyl,2-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl,3-dimethylamino-1-pyrrolidinyl, 2-ethylamino-1-pyrrolidinyl,3-propylamino-1-pyrrolidinyl, 2-n-butylamino-1-pyrrolidinyl,3-pentylamino-1-pyrrolidinyl, 2-hexylamino-1-pyrrolidinyl,3-diethylamino-1-pyrrolidinyl,3-(N-methyl-N-propylamino)-1-pyrrolidinyl,2-(N-ethyl-N-n-butylamino)-1-pyrrolidinyl, 3-acetylamino-1-pyrrolidinyl,3-propionylamino-1-pyrrolidinyl, 2-butyrylamino-1-pyrrolidinyl,3-pentanoylamino-1-pyrrolidinyl, 2-hexanoylamino-1-pyrrolidinyl,3-aminomethyl-1-pyrrolidinyl, 3-(2-aminoethyl)-1-pyrrolidinyl,2-(3-aminopropyl)-1-pyrrolidinyl, 3-(4-aminobutyl)-1-pyrrolidinyl,3-(5-aminopentyl)-1-pyrrolidinyl, 3-(6-aminohexyl)-1-pyrrolidinyl,3-(methylaminomethyl)-1-pyrrolidinyl,3-(2-ethylaminoethyl)-1-pyrrolidinyl,3-(3-propylaminopropyl)-1-pyrrolidinyl,2-(4-n-butylaminobutyl)-1-pyrrolidinyl,3-(5-pentylaminopentyl)-1-pyrrolidinyl,3-(6-hexylaminohexyl)-1-pyrrolidinyl,3-(dimethylaminomethyl)-1-pyrrolidinyl,2-(N-methyl-N-ethyl-aminomethyl)-1-pyrrolidinyl,3-(N-ethyl-N-n-butylaminomethyl)-1-pyrrolidinyl,3-methylaminomethyl-4-methyl-1-pyrrolidinyl,3-methylamino-4-methyl-1-pyrrolidinyl,3-ethylaminomethyl-4-ethyl-1-pyrrolidinyl,3-propylaminomethyl-5-propyl-1-pyrrolidinyl,3-pentylaminomethyl-5-n-butyl-1-pyrrolidinyl,3-n-butylamino-5-hexyl-1-pyrrolidinyl,3-pentylamino-4-ethyl-1-pyrrolidinyl,3-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-1-pyrrolidinyl,4-fluoro-1-piperidinyl, 3-amino-4-methyl-1-pyrrolidinyl,2-oxo-1-piperidinyl, 3-acetylaminomethyl-1-pyrrolidinyl,3-(N-ethyl-N-acetylamino)methyl-1-pyrrolidinyl,3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl,3-ethylaminomethyl-1-pyrrolidinyl, 3-acetylaminomethyl-1-pyrrolidinyl,3-(6-acetylaminohexyl)-1-pyrrolidinyl,3-(4-pentyloxycarbonylaminobutyl)-1-pyrrolidinyl,3-(5-hexyloxycarbonylaminopentyl)-1-pyrrolidinyl,3-(N-t-butoxycarbonyl-N-ethylaminomethyl)-1-pyrrolidinyl,3-(N-t-butoxycarbonyl-N-methylaminomethyl)-1-pyrrolidinyl, and the like.

The term "an amino-(C₁ -C₆)alkyl, said amino being optionallysubstituted by 1 or 2 substituents selected from the group consisting ofC₁ -C₆ alkyl group, a C₁ -C₆ alkanoyl group, and a C₁ -C₆ alkoxycarbonylgroup" includes, for example, aminomethyl, 2-aminoethyl, 1-aminoethyl,3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl,3-dimethylaminopropyl, 2-ethylaminoethyl, 4-propylaminobutyl,5-n-butylaminopentyl, 6-pentylaminohexyl, methylaminomethyl,diethylaminomethyl, 2-dipropylaminoethyl, 1-di-n-butylaminoethyl,3-dipentylaminopropyl, 4-dihexylaminobutyl, N-methyl-N-ethylaminoethyl,N-methyl-N-propylaminomethyl, formylaminomethyl, acetylaminomethyl,2-propanoylaminoethyl, 3-butyrylaminopropyl, 4-pentanoylaminobutyl,5-hexanoylaminopentyl, 6-acetylaminohexyl, propanoylaminomethyl,1-acetylaminoethyl, 2-hexanoylaminoethyl, N-acetyl-N-methyaminomethyl,N-acetyl-N-ethylaminomethyl, methoxycarbonylaminomethyl,2-ethoxycarbonylaminoethyl, 3-propoxycarbonylaminopropyl,4-t-butoxycarbonylaminobutyl, 5-pentyloxycarbonylaminopentyl,6-hexyloxycarbonylaminohexyl, t-butoxycarbonylaminomethyl,2-t-butoxycarbonylaminoethyl, 1-t-butoxycarbonylaminoethyl,N-t-butoxycarbonyl-N-methylaminomethyl,N-t-butoxycarbonyl-N-ethylaminomethyl, and the like.

The term "C₁ -C₆ alkanoyl" includes straight chain or branched chain C₁-C₆ alkanoyl groups, such as formyl, acetyl, propionyl, butyryl,pentanoyl, hexanoyl, and the like.

The term "an amino which may be substituted by 1 or 2 substituentsselected from the group consisting of a C₁ -C₆ alkyl and a C₁ -C₆alkanoyl" includes, for example, amino, methylamino, ethylamino,propylamino, t-butylamino, pentylamino, hexylamino, dimethylamino,diethylamino, di-n-propylamino, di-n-butylamino, dipentylamino,dihexylamino, N-methyl-N-n-butylamino, N-methyl-N-pentylamino,N-ethyl-N-hexylamino, acetylamino, formylamino, propionylamino,butyrylamino, pentanoylamino, hexanoylamino, N-methyl-N-acetylamino,N-ethyl-N-propionylamino, N-methyl-N-butyrylamino,N-n-propyl-N-pentanoylamino, N-ethyl-N-hexanoylamino, and the like.

The term "phenyl(C₁ -C₆)alkyl" includes, for example, benzyl,2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl,1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl,2-methyl-3-phenylpropyl, and the like.

The term "C₁ -C₆ alkoxycarbonyl" includes, for example, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, and the like.

The term "2-oxo-1,3-dioxolenemethylamino which is substituted by a C₁-C₆ alkyl" includes, for example,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-tert-butyl-2-oxo-1,3-dioxolen-4yl)methylamino,(5-pentyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-hexyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methylamino,(5-propyl-2-oxo-1,3-dioxolen-4-yl)methylamino, and the like.

The compounds of the present invention of the above general formula [1]can be prepared by various processes and preferably prepared, forexample, by the processes as shown in the following reaction schemes.##STR9## wherein R² and R³ are as defined above, R^(2') is a halogenatom or a R² group (R² is as defined above), R⁴ is a group of theformula: --COR⁹ (wherein R⁹ is a lower alkyl) or a group of the formula:--COOR¹⁰ (wherein R¹⁰ is a lower alkyl), R⁵ is a lower alkyl, R⁶ is agroup of the formula: ##STR10## (wherein R¹¹ and R¹² are each a loweralkyl) or a lower alkoxy, X² and X³ are each a halogen atom, R⁷ and R⁸are each a lower alkyl.

The halogenation of the compound [2] is carried out by reacting with ahalogenating agent in the presence or absence of a solvent. The solventincludes aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.),halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbontetrachloride, etc.), ethers (e.g. dioxane, tetrahydrofuran, diethylether, etc.), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), andthe like. The halogenating agent may be any conventional halogenatingagents which can convert hydroxy in carboxy group into a halogen atom,and includes, for example, thionyl chloride, phosphorus oxychloride,phosphorus oxybromide, phosphorus pentachloride, phosphoruspentabromide, and the like. The amounts of the compound [2] and thehalogenating agent are not specified, but, in case of using no solvent,the halogenating agent is usually used in a large excess amount, and incase of using a solvent, the halogenating agent is usually used in anamount of at least 1 mole, preferably 2 or 4 moles, per 1 mole of thecompound [2]. The reaction temperature and the reaction period of timeare not specified, either, but the reaction is usually carried out at atemperature of from room temperature to 100° C. for 30 minutes to 6hours.

The reaction of the compound [3] and the compound [4] is carried out ina suitable solvent in the presence of a basic compound. The solvent maybe any conventional solvents unless they give any undesirable effect onthe reaction, and includes, for example, water, ethers (e.g. diethylether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), alcohols(e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g.benzene, toluene, xylene, etc.), aliphatic hydrocarbons (e.g. n-hexane,heptane, cyclohexane, ligroin, etc.), amines (e.g. pyridine,N,N-dimethylaniline, etc.), halogenated hydrocarbons (e.g. chloroform,dichloromethane, carbon tetrachloride, etc.), aprotic polar solvents(e.g. DMF, DMSO, hexamethylphosphoramide (HMPA), etc.), and a mixture ofthese solvents. The basic compound includes inorganic bases (e.g.metallic sodium, metallic potassium, metallic magnesium, sodium hydride,sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, etc.), metal alcoholates(e.g. sodium methylate, sodium ethylate, etc.), and organic bases (e.g.pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline,etc.). The reaction is usually carried out at a temperature of from 0°to 150° C., preferably from room temperature to 120° C., for 0.5 to 15hours. The compound [4] is usually used in an amount of at least 1 mole,preferably 1 to 2 moles, per 1 mole of the compound [3]. The basiccompound is usually used in an amount of at least 1 mole, preferably 1to 2 moles, per 1 mole of the compound [3].

The compound [5] wherein R⁴ is the group: --COR⁹ is subjected to thereaction for removal of the group: --COR⁹ in a suitable solvent in thepresence of a basic compound. The solvent includes ethers (e.g. diethylether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatichydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatichydrocarbons (e.g. n-hexane, heptane, cyclohexane, etc.), aprotic polarsolvents (e.g. DMF, DMSO, HMPA, etc.), and the like. The basic compoundincludes ammonia gas, aqueous ammonia, primary or secondary amines (e.g.ethylamine, diethylamine, piperidine, etc.), and the like. The reactionis usually carried out at a temperature of from 0° to 150° C.,preferably from room temperature to 100° C., for 1 to 20 hours.

The compound [5] wherein R⁴ is a group: --COOR¹⁰ is subjected to thereaction for removal of the group: --COOR¹⁰ in an aqueous solution inthe presence of an acid catalyst. The acid catalyst includes mineralacids (e.g. hydrochloric acid, sulfuric acid, etc.) and organic acids(e.g. p-toluenesulfonic acid, etc.). The reaction is usually carried outat a temperature of from 0° to 150° C., preferably from room temperatureto 100° C., for 1 to 20 hours.

The reaction of the R⁴ group-removed compound and the compound [6] iscarried out in a suitable solvent. The solvent may be any solvents whichare used in the above reaction for the removal of the R⁴ group. Thereaction is usually carried out at a temperature of from 0° to 200° C.,preferably from 0° to 150° C., for 0.5 to 10 hours. The comound [6] isusually used in an equimolar to large excess amount, preferably 1 to 2moles per 1 mole of the compound [5]. In case of using a compound [6]wherein R⁶ is a lower alkoxy group, the reaction may also be carried outby using acid anhydrides (e.g. acetic anhydride) as a solvent as well asabove-mentioned solvents at a temperature of from 0° to 200° C.,preferably 0° to 170° C.

The reaction of the compound [7] and the compound [8] is carried out ina suitable solvent. The solvent may be any conventional solvents unlessthey give any undesirable effect on the reaction, and includes, forexample, alcohols (e.g. methanol, ethanol, propanol, etc.), ethers (e.g.diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.),aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatichydrocarbons (e.g. n-hexane, heptane, cyclohexane, ligroin, etc.),halogenated hydrocarbons (e.g. chloroform, methylene chloride, carbontetrachloride, etc.), aprotic polar solvents (e.g. DMF, DMSO, HMPA,etc.), and the like. The reaction is usually carried out at atemperature of from 0° to 150° C., preferably from room temperature to100° C., for 0.5 to 15 hours. The compound [8] is usually used in anamount of at least 1 mole, preferably 1 to 2 moles, per 1 mole of thecompound [7]. In the reaction, a basic compound may optionally be addedand such basic compound may be any basic compounds which are used in theabove reaction of the compound [3] and the compound [4].

The cyclization of the compound [9] is carried out in a suitable solventin the presence of a basic compound. The solvent may be any conventionalsolvents unless they give any undesirable effect on the reaction, andincludes, for example, ethers (e.g. diethyl ether, dioxane,tetrahydrofuran, monoglyme, diglyme, etc.), aliphatic hydrocarbons (e.g.n-hexane, heptane, ligroin, etc.), halogenated hydrocarbons (e.g.chloroform, methylene chloride, carbon tetrachloride, etc.), aproticpolar solvents (e.g. DMF, DMSO, HMPA, etc.), and the like. The basiccompound includes inorganic bases (e.g. metallic sodium, metallicpotassium, sodium hydride, sodium amide, sodium hydroxide, potassiumhydroxide, etc.), metal alcoholates (e.g. sodium methylate, sodiumethylate, etc.), and organic bases (e.g.1,8-diazobicyclo[5.4.0]undecene-7 (DBU), N-benzyltrimethylammoniumhydroxide, tetrabutylammonium hydroxide, etc.). The reaction is usuallycarried out at a temperature of from 0° to 150° C., preferably from roomtemperature to 120° C., for 0.5 to 5 hours. The basic compound isusually used in an amount of at least 1 mole, preferably 1 to 2 moles,per 1 mole of the compound [9].

The hydrolysis of the compound [10] can be carried out under theconditions of conventional hydrolysis, for instance, in the presence ofa basic compound (e.g. sodium hydroxide, potassium hydroxide, bariumhydroxide, potassium carbonate, etc.), a mineral acid (e.g. sulfuricacid, hydrochloric acid, nitric acid, etc.) or an organic acid (e.g.acetic acid, aromatic sulfonic acids, etc.) in a solvent such as water,alcohols (e.g. methanol, ethanol, isopropanol, etc.), ketones (e.g.acetone, methyl ethyl ketone, etc.), ethers (e.g. dioxane, ethyleneglycol, etc.), acetic acid, or a mixture thereof. The reaction isusually carried out at a temperature of from room temperature to 200°C., preferably from room temperature to 150° C., for 0.1 to 30 hours. Bythe reaction, there is produced the compound [la]. ##STR11## wherein R²and R³ are as defined above, X⁴ is a halogen atom, and R¹³ is hydrogenatom or a group of the formula: ##STR12## (wherein R¹⁴ and R¹⁵ are eachan alkyl).

The reaction of the compound [1b] and the compound [11] is carried outin an inert solvent, wherein both compounds are used in a wide range ofratio, and the compound [11] is usually used in an amount of at least 1mole, preferably 1 to 5 moles, per 1 mole of the compound [1b]. Thesolvent includes, for example, water, alcohols (e.g. methanol, ethanol,isopropanol, butanol, amyl alcohol, isoamyl alcohol, etc.), aromatichydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g.tetrahydrofuran, dioxane, diglyme, etc.), dimethylacetamide, DMF, DMSO,HMPA, N-methylpyrrolidone, and a mixture thereof. Among these solvents,the preferred one is DMF, DMSO, HMPA, and N-methylpyrrolidone. Thereaction may also be carried out in the presence of an acid-removingagent, such as inorganic carbonates (e.g. sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, potassium hydrogen carbonate,etc.) or organic bases (e.g. pyridine, quinoline, triethylamine, etc.).An alkaline methal halide (e.g. potassium fluoride, etc.) may also beadded in the reaction mixture. The reaction is usually carried out undera pressure of from 1 to 2 atm., preferably from 1 to 10 atm., at atemperature of from room temperature to 250° C., preferably from roomtemperature to 200° C., for 0.5 to 30 hours.

The compound [1b'] wherein R¹³ is a group: ##STR13## can be convertedinto the corresponding compound [1b'] wherein R¹³ is hydrogen atom bytreating the former compound with an acid or a base to decompose thechelate compound. The acid includes mineral acids (e.g. hydrochloricacid, sulfuric acid, etc.) and organic acids (e.g. acetic acid,p-toluenesulfonic acid, etc.) and the base includes mineral bases (e.g.sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate,potassium hydrogen carbonate, potassium carbonate, etc.) and organicbases (e.g. triethylamine, etc.). The reaction is preferably carried outat a temperature of from 0° C. to 150° C., preferably from 0° C. to 100°C. The acid or the base may be used in an amount of at least 1 mole,preferably 1 to 10 moles, per 1 mole of the starting compound.

In the reaction scheme-I, the starting compounds of the formula [2] arenovel or known compounds, which can be prepared, for example, by theprocess as shown in the following reaction scheme-V. ##STR14## whereinR^(2') and X² are as defined above, X⁵ and X⁶ are each a halogen atom,R¹⁹ is hydrogen atom or a lower alkyl and R²⁰ is a lower alkyl, in whichR¹⁹ and R²⁰ may be taken together to form a 5- to 7-membered ring, and Mis an alkaline metal (e.g. sodium, potassium, etc.) or a metal (e.g.silver, calcium, copper, etc.).

In case that R¹⁹ and R²⁰ of the compound [16] are taken together to forma 5- to 7-membered ring, R¹⁹ of the compound [20] is -R¹⁹ -R²⁰ -H.

The compound [16] can be prepared by reacting a starting anilinederivative of the formula [14] with a halogenating agent and thenreacting the resultant compound of the formula [14a] with a thiocompound of the formula [15].

The reaction of an aniline derivative [14] and a halogenating agent isusually carried out in a suitable solvent. The solvent may be anyconventional solvents unless they give any undesirable effect on thereaction, and includes, for example, halogenated hydrocarbons (e.g.chloroform, dichloromethane, etc.), ethers (e.g. dioxane, diethyl ether,tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene,xylene, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol,etc.), and polar solvents (e.g. DMSO, HMPA, acetonitrile, etc.). Thehalogenating agent may be any conventional halogenating agents andincludes, for example, N-bromosuccinimide, N-chlorosuccinimide, sodiumhypobromite, sodium hypochlorite, bleaching powder, thionyl chloride,tert-butyl hypochlorite, and the like. The halogenating agent is usuallyused in an amount of at least 1 mole, preferably 1 to 6 moles, per 1mole of the starting material. The reaction is usually carried out at atemperature of from -78° C. to room temperature, preferably from -60° to15° C., and usually completes within a few minutes. By the reaction,there is produced the intermediate of the formula [14a]. While theresultant compound [14a] may be separated from the reaction mixture toprovide it for a subsequent reaction, the reaction mixture is usuallyprovided for the reaction with a thio compound of the formula [15]without separating it from the reaction mixture.

The reaction of the compounds [14a] and the compound [15] is carried outin the same solvent as above-mentioned in the presence of a basiccompound. The basic compound includes inorganic bases (e.g. potassiumcarbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate, sodium amide, sodium hydride, etc.), and organic bases suchas tertiary amines (e.g. triethylamine, tripropylamine, pyridine,quinoline, etc.). The compound [15] is usually used in an amount of atleast 1 mole, preferably 1 to 1.5 moles, per 1 mole of the compound[14a]. The reaction is usually carried out at a temperature of from roomtemperature to 150° C., preferably from room temperature to 100° C., for1 to 50 hours. The reaction of the compound [16] and the compound [17]is carried out in a suitable solvent in the presence or absence of abasic compound. The solvent includes water, alcohols (e.g. methanol,ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g. benzene,toluene, xylene, etc.), ethers (e.g. dioxane, tetrahydrofuran, diglyme,etc.), polar solvents (e.g. DMF, DMSO, HMPA, N-methylpyrrolidone, etc.),or a mixture thereof. The basic compound includes inorganic carbonates(e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate,potassium hydrogen carbonate, etc.), organic bases (e.g. pyridine,quinoline, triethylamine, etc.), phase transition catalysts (e.g.phenyltriethylammonium chloride, tetramethylammonium chloride, etc.),and the like. The compound [17] is usually used in an amount of at least1 mole, preferably 1 to 2 moles, per 1 mole of the compound [16]. Thereaction is usually carried out at a temperature of from roomtemperature to 200° C., preferably from room temperature to 180° C., for0.5 to 10 hours.

The desulfuration of the compound [18] for preparing the compound [19]is usually carried out in a solvent in the presence of a suitablecatalyst. The catalyst includes, for example, aluminum-amalgam,lithium-lower alkylamine, Raney nickel, Raney cobalt, triethylphosphite, triphenyl phosphine, and the like, and preferable one isRaney nickel. The solvent includes alcohols (e.g. methanol, ethanol,isopropanol, etc.), ethers (e.g. diehtyl ether, dioxane,tetrahydrofuran, etc.), and the like. The reaction is usually carriedout at a temperature of from 0° to 200° C., preferably from roomtemperature to 100° C., for 10 minutes to 5 hours. The catalyst isusually used in an amount of from 1 to 10-fold by weight of the compound[18].

The reaction of converting the compound [19] into the compound [20] iscarried out by reacting the compound [19] with a metallic salt ofnitrous acid (e.g. sodium nitrite, potassium nitrite, etc.) in asuitable solvent in the presence of an acid, and then reacting theresultant product with a metal halide (e.g. potassium iodide, copper (I)chloride, copper (I) bromide, etc.) without separating it from thereaction mixture. The acid includes mineral acids such as hydrochloricacid, sulfuric acid and hydrobromic acid. The solvent includes water,alkanoic acids (e.g. acetic acid, etc.), ethers (e.g. dioxane,tetrahydrofuran, etc.), aromatic hydrocarbons (e.g. benzene, toluene,xylene, etc.), alcohols (e.g. methanol, ehtanol, isopropanol, etc.),halogenated hydrocarbons (e.g. chloroform, dichloromethane,dichloroethane, etc.), aprotic polar solvents (e.g. DMF, DMSO, HMPA,etc.), and a mixture thereof. The metallic salt of nitrous acid and themetal halide each is usually used in an amount of at least 1 mole,preferably 1 to 1.5 moles, per 1 mole of the compound [19]. The reactionis usually carried out at a temperature of from 0° to 150° C.,preferably from 0° to 100° C., for 10 minutes to 5 hours.

The hydrolysis of the compound [20] can be carried out in the presenceof a suitable hydrolysis catalyst, for instance, a mineral acid (e.g.sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid,etc.) or a basic compound (e.g. sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc.)in the presence or absence of a solvent. The solvent includes, forexample, water and a mixture of water and a lower alcohol (e.g.methanol, ehtanol, etc.). The reaction is usually carried out at atemperature of from 50° to 200° ]C., preferably 70° to 180° C., for 1 to10 hours.

In the reaction scheme-II, the compounds of the formula [1b] wherein R¹³is a group: ##STR15## can be prepared, for example, by the process asshown in the following reaction scheme-VI. ##STR16## wherein R³, X⁴, R¹⁴and R¹⁵ are as defined above, R^(5') is a lower alkyl or hydrogen atom,R^(13') is a group: ##STR17## and R²¹ is a lower alkyl.

The reaction of the compound [1f] and the compound [21] is carried outin a suitable solvent. The solvent includes, for example, the solventsemployed in the reaction of the R⁴ group-removed compound and thecompound [6] in the above reaction scheme-I. The reaction is usuallycarried out at a temperature of from room temperature to 200° C.,preferably from room temperature to 150° C., for 10 minutes to 5 hours.The compound [21] is usually used in an amount of at least 1 mole,preferably 1 to 10 moles, per 1 mole of the compound [1f].

The compound [1] in which the 1-pyrrolidinyl group is substituted byamino can be converted into the compound [1] in which the 1-pyrrolidinylgroup is substituted by a group: ##STR18## using the same reactioncondition as employed in the reaction of the compound [1b] and thecompound [11] in the above reaction scheme-II, and the compound [1] inwhich the 1-pyrrolidinyl group is substituted by a group: ##STR19## canalso be converted into the compound [1] in which 1-pyrrolidinyl group issubstituted by amino, by hydrolyzing the former compound under the samereaction condition as employed in the hydrolysis of the above compound[10]. ##STR20## wherein R^(2') is as defined above, R^(3') is a group:##STR21## (wherein R¹⁹ and R²⁰ are as defined above) or R³ (wherein R³is as defined above), R²⁴, R²⁵, R²⁶, R²⁷ and R²⁸ are each a lower alkyl,and X⁹ is a halogen atom.

The reaction of the compound [37] and the compound [8] can be carriedout under the same reaction condition as employed in the reaction of thecompound [1b] and the compound [11] in the above reaction scheme-II.

The reaction of the compound [29] and the compound [30a] or [30b] iscarried out in the presence or absence of a solvent, preferably in theabsence of any solvent. The solvent includes, for example, alcohols,(e.g. methanol, ethanol, isopropanol, etc.), aromatic hydrocarbons (e.g.benzene, toluene, etc.), polar solvents (e.g. acetonitrile, DMF, DMSO,HMPA, etc.). The compound [30a] or [30b] is usually used in an amount ofat least 1 mole, preferably 1 to 1.5 moles, per 1 mole of the compound[29]. The reaction is usually carried out at a temperature of from roomtemperature to 200° C., preferably from 60° to 200° C., for 0.5 to 25hours.

The cyclization of the compound [31] or [32] can be carried outaccording to various known methods such as a heating method, a methodusing an acidic compound (e.g. phosphorus oxychloride, phosphoruspentachloride, phosphorus trichloride, thionyl chloride, conc. sulfuricacid, polyphosphoric acid, etc.). In case of using the heating method,the reaction is usually carried out in a high b.p. solvent such as ahigh b.p. hydrocarbon or a high b.p. ether (e.g. tetralin, diphenylether, diethylene glycol dimethyl ether, etc.) at a temperature of from100° to 250° C., preferably from 150° to 200° C. In case of using themethod using an acidic compound, the acidic compound is usually used inan equimolar to a large excess amount, preferably 10 to 20 moles, per 1mole of the compound [31] or [32], and the reaction is usually carriedout in the presence or absence of a suitable solvent at a temperature offrom room temperature to 150° C. for 0.1 to 6 hours. The solventincludes acid anhydrides (e.g. acetic anhydride, etc.) in addition tothe solvents employed in the cyclization of the above compound [9].

The hydrolysis of the compound [1i] can be carried out under the samereaction condition as employed in the hydrolysis of the compound [10] inthe above reaction scheme-I.

The compound [1j] in which R^(3') is a group: ##STR22## can be covertedinto the corresponding compound in which R^(3') is --CH₂ R¹⁹ by treatingthe former compound under the same reaction condition as employed in thereaciton wherein the compound [18] is converted into the compound [19]in the above reaction scheme-V.

The compound [29] employed as the starting material in the abovereaciton scheme-IX can be prepared, for example, by the processes asshown in the following reaction schemes-X to XII. ##STR23## whereinR^(2'), R¹⁹, R²⁰ and X⁶ are as defined above, R²⁹ is a (lower) alkanoyl,and X⁹ is a halogen atom.

The desulfuration of the compound [16] or [29b] can be carried out underthe same reaciton conditions as employed in the desulfuration of theabove compound [18].

The reaction of converting the compound [33] into the compound [34] iscarried out in the presence of a (lower) alkanoylating agent such as a(lower) alkanoic acid (e.g. formic acid, acetic acid, propionic acid,etc.), a (lower) alkanoic acid anhydride (e.g. acetic anhydride, etc.),a (lower) alkanoic acid halide (e.g. acetyl chloride, propionyl bromide,etc.), or the like. In case of using an acid anhydride or an acid halideas the (lower) alkanoylating agent, a basic compound may be employed.The basic compound includes, for example, alkali metals (e.g. metallicsodium, metallic potassium, etc.), and hydroxides, carbonates orhydrogen carbonates thereof, organic bases (e.g. pyridine, piperidine,etc.), and the like. The reaction is carried out in the presence orabsence of a solvent, usually in the presence of a suitable solvent. Thesolvent includes, for example, ketones (e.g. acetone, methyl ethylketone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), aromatichydrocarbons (e.g. benzene, toluene, xylene, etc.), acetic acid, aceticanhydride, water, pyridine, and the like. The (lower) alkanoylatingagent is used in an amount of at least 1 mole per 1 mole of the compound[33], usually in equimolar to a large excess amount. The reaction isusually carried out at a temperature of from 0° to 150° C., preferablyfrom 0° to 100° C., for 5 minutes to 10 hours. In case of using a(lower) alkanoic acid as the (lower) alkanoylating agent, a dehydratingagent is preferably employed. The dehydrating agent includes mineralacids (e.g. sulfuric acid, hydrochloric acid, etc.), sulfonic acids(e.g. p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid,etc.), and the like. The reaction is preferably carried out at atemperature of from 50° to 120° C.

The nitration of the compound [33] or [34] is carried out by treatingthe said compound with a nitrating agent such as fuming nitric acid,conc. nitric acid, a mixed acid (e.g. nitric acid plus sulfuric acid,fuming sulfuric acid, phosphoric acid or acetic anhydride, etc.), analkali metal nitrate plus sulfuric acid, an anhydride of nitric acid andan organic acid (e.g. acetyl nitrate, benzoyl nitrate, etc.), nitrogentetraoxide, nitric acid plus mercury nitrate, nitrate of acetonecyanohydrin, an alkyl nitrate plus sulfuric acid or a polyphosphoricacid, or the like, in the presence or absence of a solvent such asacetic acid, acetic anhydride, sulfuric acid, or the like. The nitratingagent is preferably used in an amount of 1 to 1.5 moles per 1 mole ofcompound [33] or [34]. The reaction is usually carried out at atemperature of from -10° to 70° C. for 1 to 24 hours.

The hydrolysis of the compound [35] is carried out under the samereaction conditions as employed in the hydrolysis of the above compound[10].

The reaction of the compound [37a] or [38] with the compound [8] can becarried out under the same reaction conditions as employed in thereaction of the compound [1b] and the compound [11] in the abovereaction scheme-II.

The halogenation of the compound [39] can be carried out under the samereaction conditions as employed in the halogenation of the abovecompound [14].

The reaction of the compound [39a] and the compound [15] can be carriedout under the same reaction conditions as employed in the reaction ofthe compound [14a] and the compound [15].

The convertion of the compound [29b] into the compound [29a] can becarried out under the same conditions as in the convertion of thecompound [18] into the compound [19].

The reaction of converting the compound [36] into the compound [37] canbe carried out by converting the former compound into a diazonium saltthereof using sodium nitrite and an acid (e.g. sulfuric acid,hydrochloric acid hydrobromic acid, boron fluoride, etc.) in a solventsuch as a (lower) alkanoic acid (e.g. acetic acid), water, etc., andthen reacting the diazonium salt with a copper powder or a copper halide(e.g. cuprous bromide, cuprous chloride, cupric chloride, etc.) in thepresence of a hydrohalogenic acid (e.g. hydrobromic acid, hydrochloricacid, etc.), or with potassium iodide in the presence or absence of acopper powder, preferably with a copper halide in the presence of ahydrohalogenic acid. The sodium nitrite is usually used in an amount of1 to 2 moles, preferably 1 to 1.5 moles, per 1 mole of the compound[36], and the copper halide is usually used in an amount of 1 to 5moles, preferably 1 to 4 moles, per 1 mole of the compound [36]. Thereaction is usually carried out at a temperature of from -20° to 100°C., preferably from -5° to 100° C., for 10 minutes to 5 hours.

The halogen atom of X⁹ in the compound [37a] can be converted into eachother. ##STR24## wherein R^(2'), R¹⁹, R²⁰, R²⁹, X⁶ and X⁹ are as definedabove.

The hydrolysis of the compound [40] can be carried out under the samereaction conditions as employed in the hydrolysis of the above compound[10].

The halogenation of the compound [41] can be carried out under the samereaction conditions as employed in the halogenation of the compound [14]in the above reaction scheme-V.

The reaction of the compound [42] and the compound [15] can be carriedout under the same reaction conditions as employed in the reaction ofthe compound [14a] and the compound [15].

The desulfuration of the compound [43] can be carried out under the samereaction conditions as employed in the desulfuration of the compound[18] in the above reaction scheme-V. ##STR25## wherein R^(2') and X⁹ areas defined above, A is a (lower) alkylene, m is 0 or 1, X¹⁰ is a halogenatom, or a phenylsulfonyloxy which may be substituted by a lower alkyl,and R³⁵ is hydrogen atom or nitro group.

The nitration of the compound [44] in the above reaction scheme-XII canbe carried out under the same reaction conditions as employed in thenitration of the compound [34] in the above reaction scheme-X.

The reaction of the compound [44] or [45] is usually carried out using ahydride reducing agent such as sodium borohydride, lithium abluminumhydride or diborane, and the reducing agent is usually used in an amountof at least 1 mole, preferably 1 to 3 moles, per 1 mole of the compound[44] or [45]. The reduction reaction is usually carried out in asuitable solvent, for example, water, (lower) alcohols (e.g. methanol,ethanol, isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethylether, diglyme, etc.), DMSO, or the like, at a temperature of from -60°to 80° C., preferably from -30° C. to 50° C., for 10 minutes to 15hours. In case of using lithium aluminum hydride or diborane as areducing agent, an anhydrous solvent such as diethyl ether,tetrahydrofuran or diglyme is preferably employed.

The reaction of converting the compound [46] into the compound [47]wherein X¹⁰ is a halogen atom by halogenation is carried out under anyreaction conditions usually employed in halogenation of hydroxy group,and may be carried out, for example, by reacting the compound [46] witha halogenating agent in the presence or absence of a suitable inertsolvent. The halogenating agent includes, for example, hydrohalogenicacids (e.g. hydrochloric acid, hydrobromic acid, etc.),N,N-diethyl-1,2,2-trichlorovinylamide, phosphorus pentachloride,phosphorus pentabromide, phosphorus oxychloride, thionyl chloride,diethylaminosulfur trifluoride (DAST), and the like. The inert solventincludes, for example, ethers (e.g. dioxane, tetrahydrofuran, etc.),halogenated hydrocarbons (e.g. chloroform, dichloromethane, carbontetrachloride, etc.), and the like. The halogenating agent is used in anamount of at least 1 mole per 1 mole of the compound [46], usually in anequimolar to an excess amount, the reaction is usually carried out at atemperature of from 0° to 150° C., preferably from 0° to 80° C., for 10minutes to 15 hours. In case of using DAST as a halogenating agent, abasic compound such as triethylamine may be employed.

When the compound [46] is reacted with a phenylsulfonyl halide which mayhave a lower alkyl substituent on the phenyl ring, it may be convertedinto a compound [47] wherein X¹⁰ is a phenylsulfonyloxy which may besubstituted with a lower alkyl. The reaction can be carried out in asuitable solvent in the presence of a basic compound.

The solvent used in the above method includes, for example, ethers (e.g.diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.),alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatichydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatichydrocarbons (e.g. n-hexane, heptane, cyclohexane, ligroin, etc.),amines (e.g. pyridine, N,N-dimethylaniline, etc.), halogenatedhydrocarbons (e.g. chloroform, dichloromethane, carbon tetrachloride,etc.), aprotic polar solvents (e.g. DMF, DMSO, HMPA, etc.), and amixture thereof. The basic compound includes inorganic bases (e.g.metallic sodium, metallic potassium, metallic magnesium, sodium hydride,sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, etc.), metal alcoholates(e.g. sodium methylate, sodium ethylate, etc.), organic bases (e.g.pyridine, piperidine, quinoline, triethylamine, N,N-dimethylaniline,etc.), and the like. The reaction is usually carried out at atemperature of from 0° to 120° C., preferably from room temperature to100° C., for 0.1 to 5 hours. The phenylsulfonyl halide which may have alower alkyl substituent on the phenyl ring is usually used in an amountof at least 1 mole, preferably 1 to 3 moles, per 1 mole of the compound[46].

Among the above compounds [3], [5], [7], [9], [10], [1a], [1b], 1b'],[29], [31] and [32], the compounds wherein R² is a piperidinyl grouphaving oxo group can be converted into the compounds wherein R² is apiperidinyl group having hydroxy group, by reducing the formercompounds. The reduction can be carried out in a suitable solvent in thepresence of a reducing agent for hydrogenation. The reducing agentincludes, for example, sodium borohydride, lithium aluminum hydride,diborane, and the like, and is usually used in an amount of at least 1mole, preferably 1 to 5 moles, per 1 mole of the starting material to bereduced. The solvent includes, for example, water, (lower) alcohols(e.g. methanol, ethanol, isopropanol, etc.), ethers (e.g.tetrahydrofuran, diethyl ether, diglyme, etc.), and the like. Thereaction is usually carried out at a temperature of from -60° to 50° C.,preferably from -30° C. to room temperature, for 10 minutes to 5 hours.In case of using lithium alminum hydride or diborane as the reducingagent, it is preferred to employ an anhydrous solvent such as diethylether, tetrahydrofuran, diglyme. In case of using sodium borohydride asthe reducing agent, an inorganic base such as sodium hydroxide may alsobe added in the reaction mixture.

The compounds [46], [47] and [48] wherein R³⁵ is hydrogen atom can beconverted into the corresponding compounds wherein R³⁵ is nitro by thesame nitration reaction of the compound [44].

The compounds [44] and [45] can be prepared by the process as shown inthe following reaction scheme. ##STR26## wherein R^(2'), R³⁵, X⁹, M andm are as defined above, and A' is a lower alkylene, provided that thegroups (A')_(m) CH₂ -- and (A')_(m) CH₂ CH₂ -- have not more than 6carbon atoms, R³⁶ is a lower alkyl, and X¹¹ is a halogen atom.

The reduction of the compound [55] is carried out under the sameconditions as in the reduction of the compound [44] or [45]. Besides,the halogenation of the compound [56] can be carried out under the sameconditions as in the halogenation of the compound [46].

The reaction of the compound [57] and the compound [58] is usuallycarried out in an appropriate solvent in the presence of a basiccompound at a temperature of from room temperature to 200° C.,preferably from 60 to 120° C., for 1 to 24 hours. The solvent includes,for example, ethers (e.g. dioxane, tetrahydrofuran, ethylene glycoldimethyl ether, diethyl ether, etc.), aromatic hydrocarbons (e.g.benzene, toluene, xylene, etc.), lower alcohols (e.g. methanol, ethanol,isopropanol, etc.), polar solvents (e.g. dimethylformamide,dimethylsulfoxide, etc.), and the like. The basic compound includes, forexample, inorganic bases (e.g. calcium carbonate, sodium carbonate,potassium carbonate, sodium hydrogen carbonate, sodium hydroxide,potassium hydroxide, sodium amide, sodium hydride, potassium hydride,sodium methylate, sodium ethylate, etc.), amines (e.g. triethylamine,tripropylamine, pyridine, quinoline, etc.), and the like. The reactionproceeds favorably by using an alkali metal iodide (e.g. potassiumiodide, sodium iodide, etc.). The compound [58] is usually used in anequimolar to excess amount, preferably 1 to 5 moles, more preferably 1to 1.2 mole, per 1 mole of the compound [57].

The reaction of the compound [57] and the compound [17] can be carriedout under the same conditions as in the reaction of the compound [16]and the compound [17]. Besides, the hydrolysis of the compound [59] or[60] can be carried out under the same conditions as in the hydrolysisof the compound [20].

The compounds [10] in the reaction scheme-I and the compounds [1b] and[1b'] in the reaction scheme-II are useful not only as an intermediatefor preparing the present compounds [1] having antimicrobial activities,but also as an antimicrobial agent because they also have antimicrobialactivities.

In the compounds of the present invention there are optical andgeometrical isomers, and the present invention includes also theseisomers.

Among the present compounds [1], the preferable ones are the compoundswherein R³ is methyl or ethyl (in particular, methyl).

The compounds [1] can easily be converted into a salt thereof by treaingthem with a pharmaceutically acceptable acid or base. The acid includesinorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid,hydrobromic acid, etc.) and organic acids (e.g. oxalic acid, maleicacid, fumaric acid, malic acid, tartaric acid, citric acid, lactic acid,benzoic acid, methanesulfonic acid, propionic acid, etc.). The baseincludes sodium hydroxide, potassium hydroxide, calcium hydroxide,sodium carboante, potasium hydrogen carbonate, and the like.

The compound thus obtained can easily be isolated by conventionalmethods, such as extraction with solvents, dilution method,recrystallization, column chromatography, preparative thin layerchromatography, and the like.

The compounds [1] of the present invention or salts thereof showexcellent antimicrobial activity against Pseudomonas aeruginosa,anaerobic bacteria, resistant cells against various antimicrobials,clinically isolated bacteria, and gram negative and gram positivebacteria (e.g. Enterococcus faecalis, Staphylococcus pyogenes, etc.),and hence, are useful as an antimicrobial agent for the treatment ofdiseases induced by these microorganisms. These compounds show also lowtoxicity and less side effect and are characteristic in goodabsorbability and in sustained activity. Moreover, the compounds arehighly excreted via urine and hence are useful for the treatment ofurinary infectious diseases, and further because of easy excretion viabile, they are also useful for the treatment of intestinal infectiousdiseases. Besides, the compounds of this invention show improvedabsorbability into body by using them in the form of a salt such aslactate, hydrochloride, etc.

The compounds of the present invention are usually used in the form of ausual pharmaceutical preparation. The pharmaceutical preparation can beprepared in admixture with conventional pharmaceutically acceptablediluents or carriers, such as fillers, weighting agents, binding agents,wetting agents, disintegrators, surfactants, lubricating agents, and thelike. The pharmaceutical preparation includes various preparationssuitable for treatment of the diseases, for example, tablets, pills,powders, solutions, suspensions, emulsions, granules, capsules,suppositories, injections (solutions, suspensions, etc.), and the like.In the preparation of tablets, there may be used any conventionalcarriers, for example, excepients (e.g. lactose, white sugar, sodiumchloride, glucose, urea, starches, calcium carbonate, kaolin,crystalline cellulose, silicate, etc.), binding agents (e.g. water,ethanol, propanol, simple syrup, glucose solution, starch solution,gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose,potassium phosphate, polyvinylpyrrolidone, etc.), disintegrators (e.g.dry starch, sodium alginate, agar powder, laminaran powder, sodiumhydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fattyacid esters, sodium laurylsulfate, stearic monoglyceride, starches,lactose, etc.), disintegration inhibitors (e.g. white sugar, stearin,cacao butter, hydrogenated oils, etc.), absorption promoters (e.g.quaternary ammonium salts, sodium laurylsulfate, etc.), wetting agents(e.g. glycerin, starches, etc.), adsorbents (e.g. starches, lactose,kaolin, bentonite, colloidal silicates, etc.), rublicants (e.g. purifiedtalc, stearates, boric acid powder, polyethylene glycol, etc.), and thelike. The tablets may also be coated with conventional coating agents,for example, may be in the form of a sugar coated tablet, agelatin-coated tablets, an enteric coating tablet, a film coatingtablet, or a double or multiple layers tablet. In the preparation ofpills, there may be used conventional carriers, such as excipients (e.g.glucose, lactose, starches, cacao butter, hydrogenated vegetable oils,kaolin, talc, etc.), binding agents (e.g. gum arabic powder, tragacanthpowder, gelatin, ethanol, etc.), disintegrators (e.g. laminaran, agar,etc.), and the like. In the preparation of suppositories, there may beused conventional carriers, such as polyethylene glycol, cacao butter,higher alcohols, higher alcohol esters, gelatin, semi-synthetizedglycerides, and the like. In the preparation of injections, thesolutions, emulsions or suspensions of the compounds are sterilized andare preferably made isotonic with the body liquid. These solutions,emulsions and suspensions are prepared by admixing the active compoundwith a conventional diluent, such as water, aqueous lactic acidsolution, ethyl alcohol, propylene glycol, ethoxylated isostearylalcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fattyacid esters, and the like. The preparations may also be incorporatedwith sodium chloride, glucose or glycerin in an amount sufficient tomake them isotonic with the body liquid. The preparations may also beincorporated with conventional solubilizers, buffering agents,anesthetizing agents, and further, with coloring agents, preservatives,perfumes, flavors, sweeting agents, and other medicaments. Thepreparations in the form of a paste, cream or gel may be prepared byusing as a diluent white vaseline, paraffin, glycerin, cellulosederivatives, polyethylene glycol, silicone, bentonite, or the like.

The pharmaceutical preparation of the present invention may also be inthe form of an infusable or injectable solution containing the abovecompound [1] or a salt thereof (e.g. lactate, etc.), and an acid notproducing a precipitate. The acid not producing a precipitate includes,for example, lactic acid, methanesulfonic acid, propionic acid,hydrochloric acid, succinic acid, and the like, preferably lactic acid.In case of using lactic acid, the acid is usually used in an amount offrom 0.1 to 10% by weight, preferably from 0.5 to 2% by weight, based onthe weight of the above infusable or injectable solution. In case ofusing an acid other than lactic acid, the acid is usually used in anamount of from 0.05 to 4% by weight, preferably from 0.3 to 2% byweight, based on the weight of the above solution. Moreover, aconventional additive may optionally be added to the above infusable orinjectable solution. The additive includes, for example, a thickener, anabsorption promoter or inhibitor, a crystallization inhibitor, acomplex-forming agent, an antioxidant, an isotonicity-giving agent, or ahydrating agent, and the like. The pH of the solution can properly beadjusted by adding an alkali such as sodium hydroxide, and is usuallyadjusted within the range of from 2.5 to 7. The infusable or injectablesolution thus prepared has an excellent stability, and can be stored andpreserved for a long time with retaining the solution state.

The active compounds [1] or salts thereof may be contained in any amountin the preparations, and are usually contained in an amount of 1 to 70%by weight based on the whole weight of the preparations.

The pharmaceutical preparations of the present invention can beadministered in any methods. Suitable method for administration may beselected in accordance with the preparation form, age and sex of thepatients, degree of severity of the diseases, and the like. Forinstance, tablets, pills, solutions, suspensions, emulsions, granulesand capsules are administered in oral route. In case of injection, it isadministered intravenously alone or together with an auxiliary liquid(e.g. glucose, amino acid solution, etc.). The injections may also beadministered in intramuscular, intracutaneous, subcutaneous, orintraperitoneal route. Suppositories are administered in intrarectalroute.

The dosage of the pharmaceutical preparations of the present inventionmay vary according to administration methods, age and sex of thepatients, severity of the diseases, and the like, but is usually in therange of about 0.2 to 100 mg of the active compound [1] or a saltthereof per 1 kg of body weight of the patient per day. The preparationis usually administered by dividing into 2 to 4 times per day.

The present invention is illustrated by the following ReferenceExamples, Examples, Preparations, and Experiments.

REFERENCE EXAMPLE 1

To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethylsulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is addedgradually N-chlorosuccinimide (90 g) at below 15° C., and thereafter isfurther added in portions triethylamine (93 ml) at 15° C. After theaddition, the mixture is refluxed for 7 hours. After cooling, 10%aqueous sodium hydroxide (one liter) is added to the reaction mixture,and the mixture is extracted with dichloromethane. The extract is driedover magnesium sulfate and concentrated, and the resulting residue ispurified by silica gel column chromatography (solvent,dichloromethane:n-hexane=1:2). The product is recrystallized fromn-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g)as a white crystal, m.p. 60°-61° C.

REFERENCE EXAMPLE 2

A mixture of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (99 g), HMPA(130 g) and copper cyanide (48 g) is heated at 150° C. for 4 hours.After cooling, the reaction mixture is poured into a solution ofethylenediamine (50 ml) in water (500 ml), and the mixture is heated at60° C. for one hour. After cooling, the mixture is extracted with ethylacetate, and the extract is dried over magnesium sulfate andconcentrated. The resulting residue is purified by silica gel columnchromatography (solvent, dichloromethane:n-hexane=1:1), and the productis recrystallized from ethanol to give2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (28 g), as a whitecrystal, m.p. 109°-110° C.

REFERENCE EXAMPLE 3

To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile(4.0 g) in ethanol (80 ml) are added Raney nickel (40 ml) with ethanol(80 ml). The mixture is stirred at 40°-50° C. for 30 minutes, and thenfiltered. To the filtrate is added water, the reaction mixture isextracted with ethyl acetate. The extract is dried over magnesiumsulfate and concentrated. The product is recrystallized from n-hexane togive 2-amino-4,5-difluoro-3-methylbenzonitrile (2.4 g), as a whitecrystal, m.p. 114°-116° C.

REFERENCE EXAMPLE 4

Sodium nitrite (5.6 g) is added to conc. sulfuric acid (59 ml) at below70° C. The mixture is heated at 70° C. for 10 minutes and then cooled,and thereto is added dropwise a solution of2-amino-4,5-difluoro-3-methylbenzonitrile (12.3 g) in acetic acid (123ml) at below 40° C. The mixture is stirred at the same temperature for30 minutes and then added in portions to a solution of cuprous chloride(20 g) in conc. hydrochloric acid (200 ml), and thereafter is heated at80° C. for 30 minutes. After cooling, to the reaction mixture is addedice water, and ethyl acetate is distilled off. The resulting residue ispurified by silica gel column chromatography (solvent,dichloromethane:n-hexane=1:1) to give2-chloro-4,5-difluoro-3-methylbenzonitrile (8.0 g), as a white crystal,m.p. 59°-61° C.

REFERENCE EXAMPLE 5

To 2-chloro-4,5-difluoro-3-methylbenzonitrile (4.0 g) is added 60%sulfuric acid (20 ml), and the mixture is heated at 140°-150° C. for 3hours. After cooling, the reaction mixture is poured into ice water, andthe mixture is extracted with dichloromethane. The extract is dried overmagnesium sulfate and the solvent is distilled off. To the residue isadded n-hexane, and the precipitate is separated by filtration to give2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g), as a white crystal,m.p. 121°-122° C.

REFERENCE EXAMPLE 6

To 2-chloro-4,5-difluoro-3-methylbenzoic acid (3.1 g) is added thionylchloride (6 ml), and the mixture is reflexed for one hour. The mixtureis concentrated under reduced pressure to give2-chloro-4,5-difluoro-3-methylbenzoyl chloride (3.3 g).

Separately, metallic magnesium (0.38 g) is suspended in anhydrousethanol (0.8 ml) and thereto is added a few drops in carbontetrachloride. When the reaction is started, a mixture of diethylmalonate (2.3 ml), anhydorus ethanol (1.5 ml) and anhydrous toluene (6ml) is added portionwise at 50°-60° C. Thereto is added dropwise asolution of the above 2-chloro-4,5-difluoro-3-methylbenzoyl chloride(3.3 g) in anhydrous toluene (5 ml) at 0° C. After the addition, themixture is stirred at room temperature for 30 minutes. To the ractionmixture is added a mixture of conc. sulfuric acid (0.4 ml) and water (8ml) and the mixture is extracted with diethyl ether. The extract isdried over magnesium sulfate and the solvent is then distilled off togive diethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate (5.1 g).

REFERENCE EXAMPLE 7

To diethyl 2-chloro-3-methyl-4,5-difluorobenzoylmalonate (5.1 g) areadded water (10 ml) and p-toluenesulfonic acid (30 ml), and the mixtureis refluxed for 4 hours. After cooling, the mixture is extracted withdiethyl ether and the extract is dried over magnesium sulfuate. Thediethyl ether is distilled off to give ethyl2-chloro-4,5-difluoro-3-methylbenzoyl acetate (3.9 g).

REFERENCE EXAMPLE 8

To ethyl 2-chloro-4,5-difluoro-3-methylbenzoylacetate (3.9 g) are addedtriethoxymethane (3.1 g) and acetic anhydride (3.4 g), and the mixtureis heated at 150° C. for one hour. The mixture is concentrated to giveethyl 2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-ethoxyacrylate. To theproduct is added ethanol (50 ml) and thereto is added cyclopropylamine(1.1 ml) at room temperature, and the mixture is stirred for 30 minutes.Ethanol is distilled off to give ethyl2-(2-chloro-3-methyl-4,5-difluorobenzoyl)-3-cyclopropylaminoacrylate. Tothe product is added anhydrous dioxane (30 ml) and thereto is addedportionwise 60% sodium hydride (0.6 g). The mixture is stirred at roomtemperature for 30 minutes and then refluxed for one hour. The reactionmixture is poured into aquoeus saturated ammonium chloride and extractedwith dichloromethane. The extract is dried over magnesium sulfate andconcentrated to give ethyl1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3carboxylate(2.2 g).

NMR (CDCl₃) δ: 8.64 (1H, s), 8.10 (1H, t, J=10 Hz), 4.36 (2H, q, J=7.5Hz), 3.76-4.10 (1H, m), 2.76 (3H, d, J=4.5 Hz), 1.37 (3H, t, J=7.5 Hz),0.86-1.30 (4H, m).

REFERENCE EXAMPLE 9

To ethyl1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(2.2 g) are added conc. hydrochloric acid (5 ml), water (2 ml) andacetic acid (20 ml), and the mixture is refluxed for 2 hours. Aftercooling, the precipitated crystals are separated by filtration, andwashed with water, ethanol diethyl ether in this order to give1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (1.8 g) as a white crystal, m.p. 240°-243° C.

REFERENCE EXAMPLE 10

To1-cyclopropyl-6,7-difluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (1.0 g) are added triacetylborone [B(OCOCH₃)₃ ] (1.0 g) and aceticanhydride (10 ml) and the mixture is heated at 140° C. for 15 minutes.After the reaction, the mixture is concentrated and to the resultingresidue is added diethyl ether and the crystals are separated byfiltration to give6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid-B(OCOCH₃)₂ chelate (1.2 g).

NMR (CDCl₃) δ: 9.32 (1H, s), 8.23 (1H, t, J=9 Hz), 4.30-4.58 (1H, m),2.97 (3H, d, J=3 Hz), 2.03 (6H, s), 1.13-1.60 (4H, m).

REFERENCE EXAMPLE 16

Into a solution of 6-bromo-3,4-difluoro-2-methylthiomethylaniline (6.00g) in ethanol (120 ml) is suspensed Raney nickel (70 ml), and themixture is stirred at 50° C. for 30 minutes. After removing Raney nickelby filtration, the filtrate is concentrated to give3,4-difluoro-2-methylaniline (3.77 g) as a colorless oil.

NMR (CDCl₃) δ: 6.72 (1H, ddd, J=10.2 Hz, 10.2 Hz, 8.7 Hz), 6.27 (1H,ddd, J=10.2 Hz, 6.0 Hz, 2.7 Hz), 3.43 (2H, br), 2.02 (3H, d, J=2.4 Hz).

REFERENCE EXAMPLE 17

To 3,4-difluoro-2-methylaniline (3.27 g) is added acetic anhydride (50ml), and the mixture is sirred for 10 minutes. After distilling offacetic anhydride, the resulting residue is extracted withdichloromethane. The extract is washed with water, aqueous saturatedsodium hydrogen carbonate and aqueous saturated sodium chloride in thisorder, and then dried over anhydrous magnesium sulfate. After distillingoff dichloromethane, the residue is recrystallized from ethylacetate-n-hexane to give 3,4-difluoro-2-methylacetanilide (3.86 g) ascolorless needles, m.p. 145.5°-146.0° C.

REFERENCE EXAMPLE 18

3,4-Difluoro-2-methylacetanilide (100 mg) is added to ice-cooled conc.sulfuric acid (0.3 ml) and thereto is added conc. nitric acid (0.1 ml)under ice cooling, and the mixture is stirred at room temperature for 2hours. To the mixture is further added conc. nitric acid (0.1 ml), andthe mixture is stirred at room temperature overnight. To the reactionmixture is added a large amount of water, and the mixture is extractedwith dichloromethane. The extract is washed with water, aqueoussaturated sodium hydrogen carbonate and aqueous saturated sodiumchloride in this order and then dried over anhydrous magnesium sulfate.After distilling off dichloromethane, the residue is recrystallized fromethyl acetate-n-hexane to give 4,5-difluoro-6-methyl-2-nitroacetanilide(80.7 mg) as yellow needles, m.p. 152.1°-152.6° C.

REFERENCE EXAMPLE 19

4,5-Difluoro-6-methyl-2-nitroacetanilide (81 mg) is dissolved in aceticacid (2 ml) and thereto is added conc. hydrochloric acid (1 ml) at 0° C.The mixture is stirred at 100° C. overnight and then concentrated. Theresidue is neutralized with aqueous saturated sodium hydrogen carbonateand extracted with dichloromethane. The extract is washed with aqueoussaturated sodium chloride and dried over anhydrous magnesium sulfate.Dichloromethane is distilled off to give4,5-difluoro-6-methyl-2-nitroaniline (59 mg) as orange prisms, m.p.87.2°-88.0° C.

REFERENCE EXAMPLE 20

Sodium nitrite (30 mg) is added portionwise to conc. hydrochloric acid(0.32 ml), and the mixture is stirred at 70° C. for 10 minutes andcooled to room temperature and thereto is added dropwise a solution of4,5-difluoro-6-methyl-2-nitroanline (59 mg) in acetic acid (6.5 ml) atthe same temperature. The mixture is stirred at room temperature for 30minutes and thereto is added dropwise a solution of cuprous chloride(107 mg) in conc. hydrochloric acid (1.0 ml). The mixture is stirred at80° C. for 30 minutes. To the reaction mixture is added water and themixture is extracted with ethyl acetate. The extract is washed withwater, aqueous saturated sodium hydrogen caronate and aqueous saturatedsodium chloride in this order and then dried over anhydrous magnesiumsulfate. Ethyl acetate is distilled off to give2-chloro-5,6-difluoro-3-nitrotoluene (54 mg).

NMR (CDCl₃) δ: 7.58 (1H, dd, J=11.0 Hz, 8.0 Hz), 2.40 (3H,s).

REFERENCE EXAMPLE 23

To a solution of 3,4-difluoroacetanilide (85.5 g) in sulfuric acid (850ml) is added gradually with stirring potassium nitrate (55.5 g) at roomtemperature during which the temperature raises to 60° C. The mixture isstirred at 60° C. for one hour. The reaction mixture is poured into icewater, and the precipitated crystals are taken by filtration. Theprecipitates are dissolved in dichloromethane and washed with aqueoussodium hydrogen carbonate, water and aqueous saturated sodium chloridein this order and dried. The solvent is removed by concentration andwashed with n-hexane. The resulting crystals are taken by filtration anddried to give 2-nitro-4,5-difluoroaniline (54 g.).

NMR (CDCl₃) δ: 5.76-6.40 (2H, m), 6.60 (1H, dd, J=12 Hz, 7 Hz), 7.97(1H, dd, J=10.5 Hz, 8.5 Hz).

REFERENCE EXAMPLE 24

To a solution of 2-nitro-4,5-difluoroaniline (1.0 g) and dimethylsulfide(1.79 g) in dichloromethane (40 ml) is added graduallyN-chlorosuccinimide (3.82 g) with stirring at below 15° C. The mixtureis stirred for 30 minutes, and thereto is added triethylamine (2.89 g),and the mixture is refluxed for 21 hours. After allowing to cool, thereaction mixture is washed with 10% aqueous sodium hydroxide, water andaqueous sodium chloride in this order and dried. The solvent is removedby concentration, and the resulting residue is purified by silica gelcolumn chromatography (solvent, n-hexane:ethylacetate=30:1) and thenrecrystallized from n-nexane to give2-nitro-4,5-difluoro-6-methylthiomethylaniline (0.47 g) as yellowneedles, m.p. 110°-111.5° C.

REFERENCE EXAMPLE 25

Sodium nitrite (0.15 g) is added to conc. sulfuric acid (15 ml) and themixture is stirred at 70° C. for 10 minutes. To the mixture is addeddropwise a solution of 2-nitro-4,5-difluoro-6-methylthiomethylaniline(0.45 g) in acetic acid (4.5 ml). The mixture is stirred at the sametemperature for 45 minutes, and thereto is further added dropwise asolution of cuprous chloride (0.52 g) in conc. hydrochloric acid (5.2ml). The mixture is stirred at 80° C. for 1.5 hour, and the reactionmixture is poured into ice water and extracted with ethyl acetate. Theextract is washed with water and aqueous saturated sodium chloride inthis order and dried, and then the solvent is disilled off. Theresulting residue is purified by silica gel column chromatography(solvent, n-hexane:ethyl acetate=30:1) to give2-chloro-3-methylthio-4,5-difluoro-1-nitrobenzene (0.16 g).

NMR (CDCl₃) δ: 2.15 (3H, s), 3.92 (2H, dd, J=3 Hz), 7.67 (1H, dd, J=8.5Hz, 8 Hz)

REFERENCE EXAMPLE 26

2,3,6-Trifluorobenzoic acid (21.0 g) is added to conc. sulfuric acid(120 ml) under ice-cooling. To the mixture is added dropwise a solutionof potassium nitrate (14.5 g) in conc sulfuric acid (30 ml) at below 20°C. After the addition, the mixture is stirred at room temperature forone hour. The reaction mixture is poured into ice water and extractedwith diethyl ether. The extract is dried over magnesium sulfate, andthen the solvent is distilled off. The residue is recrystallized fromdichloromethane-n-hexane to give 2,5,6-trifluoro-3-nitrobenzoic acid (22g), as colorless prisms, m.p. 98°-99° C.

NMR (CDCl₃) δ: 8.11-8.23 (1H, m), 9.10 (1H, brs).

REFERENCE EXAMPLE 27

To a solution of sodium boron hydroxide (44 g) in anhydroustetrahydrofuran is added a solution of 2,5,6-trifluoro-3-nitrobenzoicacid (22 g) in anhydrous tetrahydrofuran (40 ml) at below 10° C., andthereto is further added dropwise a solution of boron trifluorideetherate (20 ml) in anhydrous tetrahydrofuran (40 ml) at below 10° C.After the addition, the mixture is stirred at room temperature for onehour. The reaction mixture is poured into ice water and extracted withdiethyl ether. The extract is dried, and then the solvent is distilledoff to give 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g).

NMR (CDCl₃) δ: 2.56 (1H, brs), 4.88 (2H, t, J=1.8 Hz), 7.92-8.04 (1H, m)

REFERENCE EXAMPLE 28

To a solution of 2,5,6-trifluoro-3-nitrobenzyl alcohol (14 g) in ethanol(64 ml) and water (7 ml) is added a mixture of4-ethoxycarbonylpiperazine (11 g), triethylamine (12.5 g) and ethanol(18 ml) at one time. The mixture is stirred at room temperatureovernight, and the resulting precipitates are separated by filtration.The crystals are washed with a small amount of diethyl ether andrecrystallized from ethanol to give3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol(8.7 g), as yellow needles, m.p. 147°-149° C.

REFERENCE EXAMPLE 29

To a solution of3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol(8.5 g) in chloroform (85 ml) is added thionyl chloride (2.7 ml) at roomtemperature. The mixture is stirred at the same temperature for 30minutes, and the reaction mixture is poured into ice water, and thenneutralized with sodium hydrogen carbonate and extracted with diethylether. The extract is dried over magnesium sulfate, and then the solventis distilled off to give2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitorbenzyl chloride(8.1 g).

NMR (CDCl₃) δ: 1.28 (3H, t, J=7.1 Hz), 3.08-3.33 (4H, m), 3.46-3.75 (4H,m), 4.18 (2H, q, J=7.1 Hz), 4.77 (2H, d, J=2.5 Hz), 7.82 (1H, dd, J=9.2Hz, 7.2 Hz).

REFERENCE EXAMPLE 30

To a solution of3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl chloride(8.1 g) in dimethylsulfoxide (90 ml) is added gradually sodium boronhydride (1.8 g) at below 30° C. The mixture is stirred at the sametemperature for one hour, and the reaction mixture is poured into icewater, and then acidified with conc. hydrochloric acid and extractedwith diethyl ether. The solvent is distilled off to give2-(4-ethoxycarbonyl-1-piperazinyl)-3,6-difluoro-5-nitrotoluene (7.1 g).

NMR (CDCl₃) δ: 1.26 (3H, t, J=7.1 Hz), 2.30 (3H, d, J=3 Hz), 2.76-3.27(5H, m), 3.50-3.75 (4H, m), 4.17 (2H, q, J=7.1 Hz), 7.60 (1H, dd, J=9.3Hz, 7.2 Hz).

REFERENCE EXAMPLE 31

To 3,6-difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrotoluene(7.1 g)are added anhydrous dimethylsulfoxide (23 ml), potassium fluoride (2.0g) and cyclopropylamine (1.5 g), and the mixture is heated at 60° C. for6 hours. The reaction mixture is poured into ice water, and extractedwith dichloromethane. The solvent is distilled off and the residue isrecrystallized from ethanol to giveN-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline(7.4 g), as orange red prisms, m.p. 97°-98° C.

NMR (CDCl₃) δ: 0.50-0.54 (2H, m), 0.66-0.74 (2H, m), 1.28 (3H, t, J=7.1Hz), 2.43 (3H, s), 2.63-2.90 (1H, m), 3.07-3.28 (4H, m), 3.47-3.77 (4H,m), 4.20 (2H, q, J=7.1 Hz), 7.53 (1H, brs), 7.70 (1H, dd, J=Hz).

REFERENCE EXAMPLE 32

ToN-cyclopropyl-2-methyl-3-(4-ethoxycarbonyl-1-piperazinyl)-4-fluoro-6-nitroaniline(7.1 g) is added diethyl ethoxymethylenemalonate (4.6 g), and themixture is reacted at 150°-170° C. for 17 hours. After cooling, thesolvent is distilled off, and the resulting residue is subjected tosilica gel column chromatography (solvent,dichloromethane:n-hexane=2:1→dichloromethane) to give diethyl[N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate(5.4 g).

REFERENCE EXAMPLE 33

To a solution of diethyl[N-cyclopropyl-N-[3-(4-ethoxycarbonyl-1-piperazinyl)-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate(1.0 g) in acetic anhydride (5 ml) is added conc. sulfuric acid (2 ml)with keeping at 50°-70° C. After stirring for 30 minutes, the reactionmixture is poured into ice water, and neutralized with potassiumcarbonate. The mixture is extracted with ethyl acetate, and the solventis distilled off, and the resulting residue is purified by silica gelcolumn chromatography (solvent, dichloromethane:methanol=10:1) and thenrecrystallized from ethyl acetate to give ethyll-cyclopropyl-7-(4-ethoxycarbonyl-1-peperazinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.19 g), as colorless prisms, m.p. 200°-202° C.

In the same manner as described in Reference Example 33 by usingappropriate starting materials, there are prepared the same compounds asin Reference Example 8.

REFERENCE EXAMPLES 39

In the same manner as described in Reference Example 28 by usingappropriate starting material, there is prepared the following compound:

3,6-Difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol, m.p.117.0°-118.5° C., orange prisms (recrystallized from ethylacetate-n-hexane).

REFERENCE EXAMPLE 40

To 3,6-difluoro-2-(3-amino-1-pyrrolidinyl)-5-nitrobenzyl alcohol (43 mg)is added acetic anhydride (0.5 ml) at room temperature. The mixture isstirred at the same temperature for 10 minutes, and the reaction mixtureis diluted with water and extracted with dichloromethane. The organiclayer is washed with water and aqueous saturated sodium chloride in thisorder and dried over anhydrous magnesium sulfate, and then solvent isdistilled off. The resulting residue is purified by silica gel columnchromatography (solvent, dichloromethane→methanol:dichloromethane=1:12)and then recrystallized from dichloromethane to give2-(3-acetylamino-1-pyrrolidinyl)-3,6-difluoro-5-nitrobenzyl alcohol (40mg), as yellow prisms, m.p. 142.5°-143.5° C.

REFERENCE EXAMPLES 41

In the same manner as described in Reference Example 29 by usingappropriate starting material, there is prepared the following compound:

2-(4-Acetylamino-1-pyrrolidinyl)-3,6-difluoro-5-nitrobenzyl chloride.

NMR (CDCl₃) δ: 7.74 (1H, dd, J=12.0 Hz, 7.5 Hz), 6.16 (1H, d, J=5.4 Hz),4.78 (1H, dd, J=11.3 Hz, 3.0 Hz), 4.69 (1H, dd, J=11.3 Hz, 3.0 Hz),4.62-4.50 (1H, m), 3.97-3.69 (2H, m), 3.67-3.50 (1H, m), 3.49-3.32 (1H,m), 2.40-2.18 (1H, m), 2.12-1.93 (1H, m), 1.98 (3H, s)

REFERENCE EXAMPLES 42

In the same manner as described in Reference Example 30 by usingappropriate starting material, there is prepared the following compound:

2-(3-Acetylamino-1-pyrrolidinyl)-3,6-difluoro-5-nitrotoluene, m.p.139.0°-140.3° C., yellow needles (recrystallized from dichloromethane).

REFERENCE EXAMPLES 43

In the same manner as described in Reference Example 31 by usingappropriate starting material, there is prepared the following compound:

N-Cyclopropyl-2-methyl-3-(3-acetylamino-1-pyrrolidinyl)-4-fluoro-6-nitroaniline,m.p. 162.5°-164.0° C., orange prisms (recrystallized from ethylacetate-n-hexane).

REFERENCE EXAMPLES 44

In the same manner as described in Reference Example 32 by usingappropriate starting material, there is prepared the following compound:

Diethyl [N-cyclopropyl-N-[3-(3-acetylamino-1-pyrrolidinyl)-4-fluoro-2-methyl-6-nitrophenyl]amino-methylene]malonate

NMR (CDCl₃) δ: 7.73 (1H, s), 7.68 (1H, d, J=11.6 Hz), 5.97 (1H, br),4.62-4.45 (1H, m), 4.12 (4H, q, J=7.2 Hz), 3.85-3.15 (5H, m), 2.42-1.95(5H, m), 1.98 (3H, s), 1.29 (6H, t, J=7.2 Hz), 0.93-0.52 (4H, m).

REFERENCE EXAMPLES 45

In the same manner as described in Reference Example 33 by usingappropriate starting material, there is prepared the following compound:

Ethyl1-cyclopropyl-7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate,m.p. 215.5°-217.0° C., white powder (recrystallized from ethanol-ethylacetate-diethyl ether).

REFERENCE EXAMPLES 54

In the same manner as described in Reference Example 28 by usingappropriate starting material, there are prepared the followingcompounds:

3,6-Difluoro-2-(3-acetamidomethyl-1-pyrrolidinyl)-5-nitrobenzyl alcohol,m.p. 120°-121° C., yellow crysals.

NMR (CDCl₃ +DMSO-d₆) δ: 1.55-1.83 (1H, m), 1.95 (3H, s), 1.99-2.10 (1H,m), 2.39-2.57 (1H, m), 3.14-3.82 (6H, m), 4.72 (2H, d, J=2.6 Hz), 7.31(1H, brs), 7.70 (1H, dd, J=7.5 Hz, 13.5 Hz).

3,6-Difluoro-2-[3-(N-methyl-N-benzylamino)-1-pyrrolidinyl]-5-nitrobenzylalcohol.

NMR (CDCl₃) δ: 7.75 (1H, dd, J=7.5 Hz, 13.1 Hz), 7.41-7.20 (5H, m),3.85-3.60 (4H, m), 3.62 (1H, d, J=13.1 Hz), 3.52 (1H, d, J=13.1 Hz),3.25-3.05 (1H, m), 2.35-1.92 (3H, m), 2.20 (3H, s).

REFERENCE EXAMPLES 55

In the same manner as described in Reference Example 29 by usingappropriate starting material, there are prepared the followingcompounds;

2,5-Difluoro-3-chloromethyl-4-[3-(N-methyl-N-benzylamino)-1-pyrrolidinyl]nitrobenzene.

NMR (CDCl₃) δ: 7.78(1H, dd, J=7.6 Hz, 13.4 Hz), 7.42-7.22 (5H, m), 4.78(1H, dd, J=2.7 Hz, 12.1 Hz), 4.67 (1H, dd, J=2.7 Hz, 12.1 Hz), 3.92-3.55(4H, m), 3.67 (1H, d, J=13.1 Hz), 3.53 (1H, d, J=13.1 Hz), 3.30-3.10(1H, m), 2.35-1.88 (2H, m), 2.22 (3H, s).

2,5-Difluoro-3-chloromethyl-4-(3-acetamidomethyl-1-pyrrolidinyl)nitrobenzene,m.p. 94°-98° C., yellow crystal,

NMR (CDCl₃ +DMSO-d₆) δ: 1.68-1.90 (1H, m), 2.07 (3H, s), 2.00-2.25 (1H,m), 2.50-2.68 (1H, m), 3.20-3.79 (6H, m), 4.78 (2H, d, J=2.6 Hz), 7.78(1H, dd, J=7.5 Hz, 13.5 Hz), 8.18 (1H, brs).

REFERENCE EXAMPLE 56

In the same manner as described in Reference Example 30 by usingappropriate starting materials, there are prepared the followingcompounds.

3,6-Difluoro-5-nitro-2-[3-(N-methyl-N-benzylamino)-1-pyrrolidinyl]toluene,

NMR (CDCl₃) δ: 7.65 (1H, dd, J=7.1 Hz, 12.8 Hz), 7.38-7.20 (5H, m),3.79-3.45 (4H, m), 3.62 (1H, d, J=13.4 Hz), 3.50 (1H, d, J=13.4 Hz),3.30-3.06 (1H, m), 2.35-2.13 (1H, m), 2.25 (3H, d, J=3.2 Hz), 2.20 (3H,s), 2.11-1.88 (1H, m).

3,6-Difluoro-5-nitro-2-(3-acetamidomethyl-1-pyrrolidinyl)-toluene, m.p.82°-84° C., yellow crystals.

NMR (CDCl₃) δ: 1.60-1.78 (1H, m), 2.00 (3H, s), 2.02-2.20 (1H, m), 2.24(3H, d, J=3.2 Hz), 2.40-2.66 (1H, m), 3.20-3.62 (6H, m), 5.67 (1H, brs),7.63 (1H, dd, J=7.5 Hz, 13.5 Hz).

REFERENCE EXAMPLES 57

In the same manner as described in Reference Example 31 by usingappropriate starting material, there are prepared the followingcompounds:

N-Cyclopropyl-2-methyl-3-[3-(N-methyl-N-benzylamino)-1-pyrrolidinyl]-4-fluoro-6-nitroaniline.

NMR (CDCl₃) δ: 7.87 (1H, s), 7.69 (1H, d, J=11.7 Hz), 7.40-7.22 (5H, m),3.81-3.41 (4H, m), 3.65 (1H, d, J=10.6 Hz), 3.55 (1H, d, J=10.6 Hz),3.24-3.08 (1H, m), 2.86-2.72 (1H, m), 2.32-2.10 (1H, m), 2.29 (3H, s),2.21 (3H, s), 2.08-1.90 (1H, m), 0.88-0.56 (3H, m), 0.51-0.41 (1H, m).

N-Cyclopropyl-2-methyl-3-(3-acetamidomethyl-1-pyrrolidinyl)-4-fluoro-6-nitroaniline.

NMR (CDCl₃) δ: 0.40-0.85 (4H, m), 1.60-1.83 (1H, m), 2.01 (3H, s),2.04-2.20 (1H, m), 2.28 (3H, s), 2.42-2.60 (1H, m), 2.70-2.88 (1H, m),3.20-3.65 (6H, m), 5.89 (1H, brs), 7.65 (1H, d, J=14.6 Hz), 7.86 (1H,brs).

REFERENCE EXAMPLES 58

In the same manner as described in Reference Example 32 by usingappropriate starting material, there is prepared the following compound:

Diethyl[N-Cyclopropyl-N-[3-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl)]-2-methyl-4-fluoro-6-nitrophenyl]aminomethylene]malonate.

NMR (CDCl₃) δ: 7.85-7.60 (2H, m), 7.40-7.16 (5H, m), 4.25-4.06 (2H, m),3.80-3.05 (8H, m), 2.19 (6H, s), 2.32-1.89 (2H, m), 1.23 (6H, t, J=7.1Hz), 1.12-0.41 (4H, m).

REFERENCE EXAMPLES 59

In the same manner as described in Reference Example 33 by usingappropriate starting material, there are prepared the followingcompounds:

Ethyl1-cyclopropyl-7-[3-(N-benzyl-N-methylamino]-1-pyrrolidinyl]-6-fluoro-8-methyl-1.4-dihydro-4-oxoquinoline-3-carboxylate,m.p. 145°-148.5° C. (decomp.) (recrystallized from ethyl acetate-diethylether), pale yellow powder.

Ethyl1-cyclopropyl-7-(3-acetamidomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate,m.p. 208°-210° C. (recrystallized from ethanol), white crystals.

REFERENCE EXAMPLE 66

To 2-chloro-5,6-difluoro-3-nitrotoluene (1.0 g) are added spray-driedpotassium fluoride (1.4 g), anhydrous dimethylsulfoxide (10 ml) andbenzene (10 ml), and the moisture is removed by azeotropic distillationtogether with benzene. Subsequently, the mixture is stirred at 170°-180°C. under argon stream for 3.5 hours. After cooling, the reaction mixtureis poured into ice water and extracted with diethyl ether. The extractis washed with water, dried and then the solvent is distilled off. Theresidue is purified by silica gel column chromatography (solvent,n-hexane) to give 2,5,6-trifluoro-3-nitrotoluene (0.45 g).

NMR (CDCl₃) δ: 2.34-2.37 (3H, m), 7.75-8.00 (1H, m).

REFERENCE EXAMPLE 67

To a solution of 3-amino-1-benzyl-4-methylpyrrolidine (9.5 g) inmethanol (190 ml) is added anhydrous t-butoxycarboxylic acid (13.0 g) atroom temperature, and the mixture is stirred for one hour. Methanol isdistilled off under reduced pressure, and to the resulting residue isadded water. The mixture is extracted with dichloromethane, and theextract is dried over magnesium sulfate and then dichloromethane isdistilled off. The residue is purified by silica gel columnchromatography (solvent, dichloromethane:methanol=19:1) to give3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (isomer A) (4.4g), as colorless prisms, m.p. 131.5°-132.7° C.

NMR (CDCl₃) δ: 1.09 (3H, d, J=6.7 Hz), 1.43 (9H, s), 1.86-2.02 (2H, m),2.62 (2H, d, J=6.1 Hz), 2.93-3.05 (1H, m), 3.56 (2H, s), 3.68 (1H, brs),4.84 (1H, brs), 7.20-7.37 (5H, m).

REFERENCE EXAMPLES 68

To 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (3.9 g) areadded ethanol (50 ml) and 10% Pd-C (780 mg), and the mixture issubjected to catalytic reduction at 60° C. under atmospheric pressure.After the catalytic reduction, the catalyst is removed off byfiltration, and the filtrate is concentrated. The resulting residue isrecrystallized from ethyl acetate-petroleum ether to give3-(t-butoxycarbonylamino)-4-methylpyrrolidine (isomer A) (2.01 g), ascolorless prisms, m.p. 86.8°-87° C.

NMR (CDCl₃) δ: 1.08 (3H, d, J=6.8 Hz), 1.45 (9H, s), 1.83-1.97 (1H, m),2.10 (1H, brs), 2.43-2.52 (1H, m), 2.52-2.81 (1H, m), 3.10-3.35 (2H, m),3.53-3.73 (1H, m), 4.69 (1H, brs).

REFERENCE EXAMPLE 69

To a solution of sodium boron hydride (51.6 g) in tetrahydrofuran (500ml) is added dropwise a solution of 2,5,6-trifluorobenzoic acid (120 g)in tetrahydrofuran (200 ml) with stirring at below 10° C., and theretois further added dropwise a solution of BF₃ ·(C₂ H₅)₂ O (232 ml) intetrahydrofuran (500 ml) under ice cooling. The mixture is stirred atroom temperature overnight. The reaction mixture is poured into icewater (1.5 liter) and is extracted with diethyl ether. The extract isdried over magnesium sulfate and the solvent is distilled off underreduced pressure to give 2,3,6-trifluorobenzyl alcohol (112.7 g), aspale yellow oil, b.p. 112° C. (30 mmHg).

REFERENCE EXAMPLE 70

To a solution of 2,3,6-trifluorobenzyl alcohol (41 g) in dichloromethane(100 ml) is added dropwise a solution of thionyl chloride (50 ml) indichloromethane (80 ml) under ice cooling with stirring, and the mixtureis stirred at room temperature overnight. To the mixture is addedtriethylamine (10 ml), and the solvent is distilled off under reducedpressure to give 2,3,6-trifluorobenzyl chloride (28.6 g), as colorlessoil, b.p. 63° C. (13 mmHg).

NMR (CDCl₃) δ: 4.66 (2H, s), 6.62-6.93 (1H, m), 7.04-7.26 (1H, m).

REFERENCE EXAMPLE 71

To a solution of sodium cyanide (1.94 g) in water (4 ml) is added withphenyltriethylammonium chloride (0.09 g), and thereto is added withstirring 2,3,6-trifluorobenzyl chloride (5.0 g), and the mixture isstirred at 90° to 100° C. for 40 minutes. The reaction mixture is pouredinto water (20 ml) and is extracted with diethyl ether. The extract isdried over potassium carbonate and the solvent is distilled off to give2-(2,3,6-trifluorophenyl)acetonitrile (3.1 g), b.p. 80°-85° C. (5 mmHg).

NMR (CDCl₃) δ: 3.76 (2H, d, J=0.8 Hz), 6.89-6.98 (1H, m), 7.11-7.26 (1H,m).

REFERENCE EXAMPLE 72

2-(2,3,6-Trifluorophenyl)acetonitrile (13.3 g) is dissolved in ethanol(20 ml), and thereto is carefully added conc. sulfuric acid (8.5 ml),and the mixture is refluxed at 125° C. for 7 hours. After cooling, thereaction mixture is fractionated with diethyl ether and water. The etherlayer is washed with aqueous saturated sodium chloride and dried overmagnesium sulfate and then concentrated under reduced pressure to giveethyl 2-(2,3,6-trifluorophenyl)acetate (16.3 g), as colorless oil.

NMR (CDCl₃) δ: 1.27 (3H, t, J=7.1 Hz), 3.72 (2H, d, J=1.2 Hz), 4.19 (2H,q, J=7.1 Hz), 6.78-6.90 (1H, m), 7.00-7.16 (1H, m).

REFERENCE EXAMPLE 73

Ethyl 2-(2,3,6-trifluorophenyl)acetate (16.2 g) is dissolved in ethanol(60 ml). The mixture is stirred and thereto is added 3N sodium hydroxide(200 ml), and the mixture is stirred at 70° C. for one hour. Aftercooling, 6N hydrochloric acid (120 ml) is added to the mixture. Theresulting white powdery precipitates are dissolved by adding theretodiethyl ether. The diethyl ether layer is separated and dried overmagnesium sulfate and then concentrated under reduced pressure to give2-(2,3,6-trifluorophenyl)acetic acid (13.9 g), as white crystals.

NMR (CDCl₃) δ: 3.79 (2H, s), 6.79-6.91 (1H, m), 7.02-7.18 (1H, m), 9.75(1H, s).

REFERENCE EXAMPLE 74

Lithium aluminum hydride (0.8 g) is suspended in dry diethyl ether (5ml) and the mixture is stirred. To the mixture is added dropwise asolution of 2-(2,3,6-trifluorophenyl)acetic acid (2.0 g) in dry diethylether (15 ml), and the mixture is refluxed for 30 minutes. To thereaction mixture are added water (0.8 ml), 10% aqueous sodium hydroxide(0.8 ml) and water (1.6 ml) in this order, and the mixture is stirred atroom temperature. To the mixture is added diethyl ether (10 ml), and theresulting precipitates are separated by filtration and washed withtetrahydrofuran. The washing liquid and the filtrate are combined andthen concentrated under reduced pressure to give2-(2,3,6-trifluorophenyl)ethyl alcohol (1.9 g), as colorless oil.

NMR (CDCl₃) δ: 1.75 (1H, s), 2.98 (3H, t, J=6.7 Hz), 3.85 (2H, t, J=6.7Hz), 6.74-6.87 (1H, m), 6.93-7.09 (1H, m).

REFERENCE EXAMPLE 75

To a solution of 2-(2,3,6-trifluorophenyl)ethyl alcohol (1.5 g) inmethylene chloride (10 ml) are added with stirring p-toluenesulfonylchloride (2.2 g) and triethylamine (2.0 ml), and the mixture is stirredat room temperature for 5 hours. The reaction mixture is poured intowater and is extracted with diethyl ether. The ether layer is washedwith aqueous saturated sodium hydrogen carbonate and aqueous saturatedsodium chloride and dried over magnesium sulfate and then concentratedunder reduced pressure. The resulting residue is purified by silica gelcolumn chromatography (solvent, methylene chloride) and recrystallizedfrom diethyl ether-n-hexane to give1-[2-(p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (3.4 g), ascolorless prisms, m.p. 73°-74° C.

NMR (CDCl₃) δ: 2.44 (3H, s), 3.03 (3H, t, J=6.5 Hz), 4.23 (2H, t, J=6.5Hz), 6.70-6.82 (1H, m), 6.93-7.09 (1H, m), 7.29 (2H, d, J=8.5 Hz), 7.70(2H, d, J=8.5 Hz).

REFERENCE EXAMPLE 76

Lithium aluminum hydride (5.6 g) is suspended in dry diethyl ether (70ml) and thereto is added dropwise with stirring a solution of1-[2-(p-toluenesulfonyloxy)ethyl]-2,3,6-trifluorobenzene (23.3 g) in drydiethyl ether (170 ml) at below 10° C., and the mixture is stirred atroom temperature for one hour. To the reaction mixture are added water(5.6 ml), 10% aqueous sodium hydroxide (10.0 ml) and water (5.6 ml) inthis order, and the mixture is stirred at room temperature for 30minutes. The resulting white precipitates are filtered off, and thefiltrate is concentrated under atmospheric pressure to give2,3,6-trifluoro-1-ethylbenzene (13.2 g), as colorless oil.

NMR (CDCl₃) δ: 1.22 (3H, t, J=7.1 Hz), 2.72 (2H, q, J=7.1 Hz), 6.71-6.82(1H, m), 6.87-7.03 (1H, m).

REFERENCE EXAMPLE 77

2,3,6-Trifluoro-1-ethylbenzene (1.09 g) is dissolved in conc. sulfuricacid (5.5 ml), and thereto is added with stirring a mixture of potassiumnitrate (0.83 g) in conc. sulfuric acid (4 ml) at room temperature, andthe mixture is stirred at the same temperature for one hour. Thereaction mixture is poured into cold water (100 ml) and is extractedwith diethyl ether. The ether layer is washed with aqueous saturatedsodium chloride and dried over magnesium sulfate and then concentratedunder reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene(1.14 g), as yellow oil.

NMR (CDCl₃) δ: 1.27 (3H, t, J=7.6 Hz), 2.77-2.89 (2H, m), 7.83 (1H, dd,J=8.0 Hz, 16.2 Hz).

REFERENCE EXAMPLE 80

In the same manner as described in Reference Example 67 by using anappropriate starting material, there is prepared the following compound.

3-(t-Butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (isomer B),colorless needles, m.p. 83°-83.5° C. (recrystallized from n-hexane).

NMR (CDCl₃) δ: 0.93 (3H, d, J=6.98 Hz), 1.44 (9H, s), 2.14-2.54 (3H, m),2.60-2.93 (2H, m), 3.58 (2H, dd, J=13.03 Hz, 14.91 Hz), 4.07-4.31 (1H,m), 4.61-4.82 (1H, m), 7.14-7.39 (5H, m).

REFERENCE EXAMPLE 81

In the same manner as described in Reference Example 68 by using anappropriate starting material, there is prepared the following compound.

3-(t-Butoxycarbonylamino)-4-methylpyrrolidine (isomer B), b.p. 106°-109°C. (0.25 mmHg).

NMR (CDCl₃) δ: 0.97 (3H, d, J=6.9 Hz), 1.45 (9H, s), 1.93 (1H, brs),2.10-2.33 (1H, m), 2.61-2.79 (1H, m), 3.04-3.33 (2H, m), 3.97-4.21 (1H,m), 4.63-4.87 (1H, m).

REFERENCE EXAMPLE 82

In the same manner as described in Reference Example 32 by using anappropriate starting material, there is prepared the following compound.

Diethyl[N-cyclopropyl-N-[3-(4-methyl-1-piperazinyl)-2-ethyl-4-fluoro-6-nitrophenyl)aminomethylene]malonate

EXAMPLE 1

To6,7-difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid-B(OCOCH₃)₂ chelate (1.2 g) are added3-(N-benzyl-N-methylamino)-1-pyrrolidine (1.73 g) and dimethylacetamide(6 ml), and the mixture is reacted at 50° C. for 20 hours. Afterconcentrating, the resulting residue is dissolved in acetone (20 ml) andthereto is added conc. hydrochloric acid (5 ml), and the mixture isstirred at room temperature for 30 minutes. After the solvent isdistilled off, to the residue is added water, and the mixture isextracted with dichloromethane. The aqueous layer is taken andneutralized with aqueous sodium hydrogen carbonate, and is extractedwith dichloromethane. The extracts are combined and dried over magnesiumsulfate. After removing the solvent, the resulting residue isrecrystallized from ethanol-diethyl ether to give7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.1 g), as pale yellow powder, m.p. 160.8°-161.3° C. PG,78

EXAMPLE 2

6,7-Difluoro-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (1.8 g) is suspended in N-methylpyrrolidone (5 ml) and thereto isadded 3-(N-benzyl-N-methylamino)-1-pyrrolidine (4.0 g), and the mixtureis stirred at 150° C. for 3 hours. After the reaction, the reactionmixture is concentrated, and the resulting residue is recrystallizedfrom ethanol-diethyl ether to give7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-1-cyclorpopyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.1 g), as pale yellow powder, m.p. 160.8°-161.3° C.

EXAMPLE 3

To ethyl1-cyclopropyl-7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate(0.86 g) is added 10% aqueous sodium hydroxide (7 ml), and the mixtureis refluxed for 5 hours. After cooling, the mixture is acidified withdiluted hydrochloric acid and is extracted with dichloromethane. Theaqueous layer is adjusted to about pH 7.5 with sodium hydrogencarbonate, and the resulting precipitates are recrystallized fromethanol-diethyl ether to give7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.32 g), as pale yellow powder, m.p. 160.8°-161.3° C.

EXAMPLE 4

In the same manner as described in Examples 1, 2 and 3 by usingappropriate starting material, there are prepared the followingcompounds:

(1)7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 201.5°-203.0° C., pale yellow powder (recrystallized fromethanol-diethyl ether)

(2)1-Cyclopropyl-7-(4-hydroxy-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 234°-236° C. (recrystallized from chloroform-ethanol), paleyellow crystals.

(3)1-Cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (isolmer A), m.p. 226°-232° C., yellow powder(recrystallized from ethyl acetate-ethanol).

NMR (DMSO-d₆) δ: 1.18 (3H, d, J=6.7 Hz), 2.62 (3H, s), 7.72 (1H, d,J=13.4 Hz), 8.79 (1H, s).

(4)1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 195°-200° C. (recrystallized from ethylacetate-methanol), yellow crystals.

(5)1-Cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 185.5°-187.5° C. (decomp.) (recrystallized fromethanol-diethyl ether), white powder.

(6)1-Cyclopropyl-7-[3-(5-methyl-2-oxo-1,3-dioxolene-4-yl)methylamino-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid. (7)1-Cyclopropyl-7-[3-(N-benzyl-N-methylamino)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 160.8°-161.3° C. (recrystallized from ethanol-diethyl ether),pale yellow powder.

(8)1-Cyclopropyl-7-(4-oxo-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 247°-250° C. (recrystallized from chloroform-ethanol), whitecrystals.

(9)1-Cyclopropyl-7-(3-acetamidomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p., 192°-194° C. (recrystallized from chloroform-methanol),white crystals.

(10)1-Cyclopropyl-7-(3-t-butoxycarbonylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 131°-135° C. (recrystallized from methanol), white powder.

(11)1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 195°-200° C. (recrystallized from ethylacetate-methanol), white powder.

(12)1-Cyclopropyl-7-[3-(N-ethylacetamido)methyl-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 167°-169° C. (recrystallized from ethanol), pale yellowcrystals.

(13)1-Cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride, m.p. 267°-271° C. (recrystallized frommethanol-acetonitrile), yellow powder.

(14)1-Cyclopropyl-7-(3,5-dimethyl-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 176°-179° C. (recrystallized from ethanol), pale yellowprisms.

(15)1-Cyclopropyl-7-(4-fluoro-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 208°-210° C. (recrystallized from ethanol), colorlessneedles.

(16)1-Cyclopropyl-7-[3-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylamino-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

(17)1-Cyclopropyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

(18)1-Cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-ethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

(19)1-Cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (isomer B), m.p. 209°-213° C. (recrystallized fromethyl acetate-ethanol), yellow powder.

NMR (DMSO-d₆) δ: 1.15 (3H, d, J=6.9 Hz), 2.76 (3H, s), 7.70 (1H, d,J=13.7 Hz), 8.77 (1H, s).

(20)1-Cyclopropyl-7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (isomer A), m.p. 157°-160° C. recrystallized from ethyl acetate),yellow crystal.

NMR (CDCl₃) δ: 1.20 (3H, d, J=6.6 Hz), 2.57 (3H, s), 7.91 (1H, d, J=13.3Hz), 9.15 (1H, s).

(21)1-Cyclopropyl-7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (isomer B), m.p. 199°-202° C. (recrystallized from ethyl acetate),yellow powder.

NMR (CDCl₃) δ: 1.12 (3H, d, J=6.6 Hz), 2.58 (3H, s), 7.85 (1H, d, J=13.6Hz), 8.87 (1H, s).

(22)1-Cyclopropyl-7-(3-t-butoxycarbonylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, m.p. 117°-120° C. (recrystallized from ethanol), pale yellowprisms.

EXAMPLE 5

1-Cyclopropyl-7-(4-oxo-1-piperidyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.25 g) is dissolved in 1% aqueous sodium hydroxide (28 ml), andthereto is added sodium boron hydroxide (0.1 g) at room temperature. Themixture is stirred at the same temperature for 30 minutes, and theresulting mixture is poured into ice water and then acidified with conc.sulfuric acid. The mixture is extracted with dichloromethane, and thesolvent is distilled off. The resulting residue is crystallized byadding thereto ethyl acetate, and then recrystallized fromchloroform-methanol to give1-cyclopropyl-7-(4-hydroxy-1-piperidyl)-6-fluoro-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylicacid (0.16 g), as pale yellow crystals, m.p. 234°-236° C.

EXAMPLE 6

To1-cyclopropyl-7-[3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.1 g) are added 10% hydrochloric acid (4 ml) and ethanol (2 ml),and the mixture is reacted at 70° C. for 10 minutes. Afterconcentrating, the resulting residue is crystallized by adding theretodiethyl ether and then recrystallized from ethyl acetate-methanol togive1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (45 mg), as yellow crystals, m.p. 195°-200° C.

EXAMPLE 7

To1-cyclopropyl-7-[3-(N-ethylacetamido)methyl-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (0.22 g) is added 5% aqueous sodium hydroxide (10ml), and the mixture is refluxed for 24 hours. After cooling, theinsoluble materials are filtered off, and the filtrate is acidified withconc. hydrochloric acid. The mixture is extracted with dichloromethane,and the aqueous layer is made alkaline with aqueous sodium hydroxide,and thereto is added t-butoxycarboxylic anhydride (200 mg). The mixtureis stirred at room temperature for 30 minutes. The reaction mixture isacidified with 10% hydrochloric acid and is extracted withdichloromethane. After removing the solvent by concentration, to theresulting residue are added 10% hydrochloric acid (5 ml) and methanol(10 ml), and the mixture is heated at 70° C. for 30 minutes. Afterconcentrating, the resulting residue is recrystallized frommethanol-acetonitrile to give1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid hydrochloride (30 mg), as yellow crystals, m.p. 267°-271° C.

EXAMPLE 8

To1-cyclopropyl-7-(3-amino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.38 g) are added formic acid (3 ml), 37% formalin (3 ml) andsodium formate (0.4 g), and the mixture is refluxed for 5 hours. Aftercooling, the reaction mixture is poured into ice water and adjusted tobelow pH 8 with aqueous sodium hydrogen carbonate, and the mixture isextracted with dichloromethane. After removing the solvent byconcentration, the resulting residue is recrystallized fromethanol-diethyl ether to give1-cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid (0.1 g), as white powder, m.p. 185.5°-187.5° C. (decomp.)

In the same manner as described above using appropriate startingmaterials, there are prepared the same compounds as 1st compound in 7thand 13th in Example 4.

EXPERIMENT (Antimicrobial Activity in In Vitro)

The antimicrobial activity of the test compounds as mentioned below wastested by measuring minimum inhibitory concentration (MIC) by the serialdilution method on agar plate [cf. Chemotherapy, 22, 1126-1128 (1974)].The microorganisms were used in a concentration of 1×10⁸ cells/ml (O.D.660 mμ, 0.07-0.16) and 1×10⁶ cells/ml (100 folds dilution). When S.penumoniae type II and S. pneumoniae type III were used as the testmicroorganism, the medium contained 5% horse blood. The results areshown in Table 1.

[Test Compound]

1.7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

2.1-Cyclopropyl-7-(3-acetamidomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

3.1-Cyclopropyl-7-(4-oxo-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

4.1-Cyclopropyl--(4-hydroxy-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxquinoline-3=l-carboxylic acid

5.1-Cyclopropyl-7-[3-(t-butoxycarbonylaminomethyl)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

6.1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

7.1-Cyclopropyl-7-[3-(N-methyl-N-benzylamino)-1-pyrrolidinyl]-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

8.1-Cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

9.1-Cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4dihydro-4-oxoquinoline-3-carboxylicacid

10.1-Cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4oxoquinoline-3-carboxylicacid hydrochloride (isomer A)

11.1-Cyclopropyl-7-(3,5-dimethyl-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

12.1-Cyclopropyl-7-(4-fluoro-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid

[Test Microorganisms]

A: Staphylococcus aureus FDS 209A

B: Staphylococcus pyrogens IID S-23

C: Staphylococcus pneumoniae type II

D: Staphylococcus pneumoniae type III

E: Pseudomonas aeruginosa E-2

F: Bacteroides fragilis GM7000

G: Eubacterium limosum ATCC 8496

H: Peptococcus anaerobis GM1003

I: Propionibacterium acnes ATCC 6919

J: Propionibacterium granulosum ATCC 25564

K: Enterococcus faecalis

                  TABLE 1                                                         ______________________________________                                                         Test                                                         Test  Test Compd.                                                                              Compd.    Test Compd.                                                                            Test Compd.                               micro-                                                                              No. 1      No. 2     No. 3    No. 4                                     organ-                                                                              1 × 10.sup.6                                                                       1 × 10.sup.6                                                                      1 × 10.sup.6                                                                     1 × 10.sup.6                        isms  cells/ml   cells/ml  cells/ml cell/ml                                   ______________________________________                                        A     0.048      0.024     <0.006   0.012                                     B     0.048      0.024     0.097    0.048                                     C     --         --        --       --                                        D     --         --        --       --                                        E     0.195      --        1.56     0.78                                      F     --         --        --       --                                        G     --         --        --       --                                        H     --         --        --       --                                        I     --         --        --       --                                        J     --         --        --       --                                        K     --         --        --       --                                        ______________________________________                                                         Test                                                         Test  Test Compd.                                                                              Compd.    Test Compd.                                                                            Test Compd.                               micro-                                                                              No. 5      No. 6     No. 7    No. 8                                     organ-                                                                              1 × 10.sup.6                                                                       1 × 10.sup.6                                                                      1 × 10.sup.6                                                                     1 × 10.sup.6                        isms  cells/ml   cells/ml  cells/ml cell/ml                                   ______________________________________                                        A     0.048      <0.006    0.048    0.024                                     B     0.195      <0.006    0.195    0.048                                     C     --         --        --       --                                        D     --         --        --       --                                        E     --         0.39      --       0.39                                      F     --         --        --       --                                        G     --         --        --       --                                        H     --         --        --       --                                        I     --         --        --       --                                        J     --         --        --       --                                        K     --         --        --       --                                        ______________________________________                                                         Test                                                         Test  Test Compd.                                                                              Compd.    Test Compd.                                                                            Test Compd.                               micro-                                                                              No. 9      No. 10    No. 11   No. 12                                    organ-                                                                              1 × 10.sup.6                                                                       1 × 10.sup.6                                                                      1 × 10.sup.6                                                                     1 × 10.sup.6                        isms  cells/ml   cells/ml  cells/ml cell/ml                                   ______________________________________                                        A     <0.006     0.024     0.097    0.012                                     B     0.012      0.024     --       --                                        C     --         --        --       --                                        D     --         --        --       --                                        E     0.78       0.195     --       0.78                                      F     --         --        --       --                                        G     --         --        --       --                                        H     --         --        --       --                                        I     --         --        --       --                                        J     --         --        --       --                                        K     --         --        --       --                                        ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##STR27## wherein R² is a 1-pyrrolidinyl group of the formula: ##STR28## wherein R^(I) is an amino-(C₁ -C₆) alkyl group, said amino group may be substituted by one C₁ -C₆ alkyl group, or an amino group which may be substituted by one C₁ -C₆ alkyl group; and R^(J) is hydrogen atom or a C₁ -C₆ alkyl group or a 1-piperidinyl group which may have one substituent selected from the group consisting of oxo, hydroxy, and halogen, and R³ is methyl, or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein R^(I) is an amino group which may be substituted by one C₁ -C₆ alkyl group, and R^(J) is hydrogen atom.
 3. The compound according to claim 1, wherein R^(I) is an amino-(C₁ -C₆)alkyl group, said amino group being substituted by one C₁ -C₆ alkyl group, and R^(J) is hydrogen atom.
 4. The compound according to claim 1, wherein R^(I) is an amino group, and R^(J) is a C₁ -C₆ alkyl group.
 5. The compound according to claim 1, wherein R^(I) is an amino group, and R^(J) is hydrogen atom.
 6. The compound according to claim 1, wherein R² is a 1-piperidinyl group which may have a substituent selected from the group consisting of oxy, hydroxy and a halogen atom.
 7. A compound of the formula: ##STR29## wherein R² has the formula ##STR30## wherein R^(I) is an amino-(C₁ -C₆) alkyl group, said amino group may be substituted by one C₁ -C₆ alkyl group, or an amino group which may be substituted by one C₁ -C₆ alkyl group; and R^(J) is hydrogen atom or a C₁ -C₆ alkyl group; or a 1-piperidinyl group which may have one substituent selected from the group consisting of oxo, hydroxy, and halogen, provided that when R^(I) is amino, R^(J) is not a hydrogen atom, and R³ is methyl, or a pharmaceutically acceptable salt thereof.
 8. The compound according to claim 7, wherein R^(I) is an amino group which is substituted by one C₁ -C₆ alkyl group and R^(J) is hydrogen atom.
 9. The compound according to claim 7, wherein R^(I) is an amino-(C₁ -C₆)alkyl group, said amino group being substituted by one C₁ -C₆ alkyl group, and R^(J) is hydrogen atom.
 10. The compound according to claim 7, wherein R^(I) is an amino group, and R^(J) is a C₁ -C₆ alkyl group.
 11. The compound according to claim 7, wherein R² is a 1-piperidinyl group which may have a substituent selected from the group consisting of oxo, hydroxy and a halogen atom.
 12. A compound of the formula: ##STR31## wherein R² is a 1-pyrrolidinyl group which is substituted by 1 to 3 substituents selected from the group consisting of (i) a C₁ -C₆ alkyl group, (ii) an amino-(C₁ -C₆) alkyl group, said amino group may be substituted by one or two C₁ -C₆ alkyl groups, and (iii) an amino group which may be substituted by one or two C₁ -C₆ alkyl groups, and R³ is a C₁ -C₆ alkyl group, or a pharmaceutically acceptable salt thereof.
 13. The compound according to claim 12, wherein R² is a 1-pyrrolidinyl group of the formula: ##STR32## wherein R^(I) is an amino-(C₁ -C₆)alkyl group, said amino group may be substituted by 1 or 2 C₁ -C₆ aklyl groups, or an amino group which may be substituted by 1 or 2 C₁ -C₆ alkyl groups; and R^(J) is hydrogen atom or a C₁ -C₆ alkyl group.
 14. The compound according to claim 13, wherein R^(I) is an amino group which may be substituted by one C₁ -C₆ alkyl group.
 15. The compound according to claim 13, where R^(I) is an amino-(C₁ -C₆)alkyl group, said amino group being substituted by one C₁ -C₆ alkyl group, and R^(J) is hydrogen atom.
 16. The compound according to claim 14, wherein R³ is methyl.
 17. The compound according to claim 15, wherein R³ is methyl.
 18. A compound of the formula: ##STR33## wherein R² is a 1-piperidinyl group which may have 1 to 3 substituents selected from the group consisting of oxo, hydroxy, a halogen and a C₁ -C₆ alkyl, and R³ is a C₁ -C₆ alkyl group, or a pharmaceutically acceptable salt thereof.
 19. The compound according to claim 18, wherein R² is a 1-piperidinyl group which is substituted by one halogen atom.
 20. The compound according to claim 19, wherein R³ is methyl.
 21. The compound according to claim 18, wherein R² is a 1-piperidinyl group which is substituted by one substituent selected from hydroxy and oxo groups.
 22. 1-Cyclopropyl-7-(4-fluoro-1-piperidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 23. 7-(3-Amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 24. 1-Cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 25. 1-Cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 26. 1-Cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 27. 1-Cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
 28. An antimicrobial composition which comprises as an esstential active ingredient an effective antimicrobial amount of a compound as defined in claim 1 in admixture with a pharmaceutically acceptable diluent or carrier.
 29. An antimicrobial composition which comprises as an essential active ingredient an effective antimicrobial amount of the compound defined in claim 7 in admixture with a pharmaceutically acceptable diluent or carrier.
 30. An antimicrobial composition which comprises as an essential active ingredient an effective antimicrobial amount of a compound selected from the group consisting of 7-(3-amino-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-7-(3-aminomethyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-7-(3-methylamino-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-7-(3-ethylaminomethyl-1-pyrrolidinyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-cyclopropyl-7-(3-amino-4-methyl-1-pyrrolidinyl)-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, and 1-cyclopropyl-7-(4-fluoro-1-piperidinyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in admixture with a pharmaceutically acceptable diluent or carrier. 